The purpose of this paper is to explain how young firms in an emerging market create sustainable ... more The purpose of this paper is to explain how young firms in an emerging market create sustainable competitive advantage through innovation. The study through the Resource-Based View theory examines the effect of innovation practices on sustainable competitive advantage of young firms in Vietnam. Data were collected from 289 young firms in Vietnam. PLS SEM using Smart PLS 3.0 software were used to analyze and examine the hypotheses. The results indicated that three direct effects between innovation practices which are strategy innovation, process innovation, system innovation and sustainable competitive advantage were significant while the effect of organization innovation and technology innovation on sustainable competitive advantage were not significant in this study. This finding not only created important empirical evidence contributing to the current stock of knowledge but also opens up the important direction for young firms who are striving to achieve sustainable competitive advantage in the current context.
Niemann-Pick disease (NPD) type A is a fatal autosomal recessive lysosomal storage disorder. This... more Niemann-Pick disease (NPD) type A is a fatal autosomal recessive lysosomal storage disorder. This rare condition impairs the metabolization of lipids, leading to their accumulation within the cells. Consequently, it causes growth retardation, pancytopenia, and cellular malfunctioning in various organ systems, including ocular, hepatic, pulmonary, brain, and neuronal tissues. Although rare, these patients present in both emergency and outpatient settings. Here, we report the case of a seven-month-old male infant who presented to the emergency department with continuous fever for one week, poor feeding, and failure to thrive. After a thorough history, examination, and laboratory workup, NPD type A was diagnosed. The patient received symptomatic therapy with the continuation of conservative management. In addition, the parents received detailed counseling regarding the genetics, progressive disease course, and prognosis of this condition.
Most recently, an outbreak of severe pneumonia caused by the infection of 2019-nCoV, a novel coro... more Most recently, an outbreak of severe pneumonia caused by the infection of 2019-nCoV, a novel coronavirus first identified in Wuhan, China, imposes serious threats to public health. Upon infecting host cells, coronaviruses assemble a multi-subunit RNA-synthesis complex of viral non-structural proteins (nsp) responsible for the replication and transcription of the viral genome. Therefore, the role and inhibition of nsp12 are indispensable. Since there is no crystallographic structure of RdRp is available, so, here, we present the 3-dimensional structure of the 2019-nCoV nsp12 polymerase using a computational approach. nsp12 of 2019-nCoV possesses an architecture common to all viral polymerases as well as a large N-terminal extension. This structure illuminates the assembly of the coronavirus core RNA-synthesis machinery, provides key insights into nsp12 polymerase catalysis and fidelity, and acts as a template for the design of novel antiviral therapeutics. Besides, the experimental s...
Here we reported recent advancement in the 3D structures of G protein-coupled receptors (GPCR) wh... more Here we reported recent advancement in the 3D structures of G protein-coupled receptors (GPCR) which act as major receptors in the spread of many diseases like HIV-1 and HIV-2. GPR15 is one among the GPCRs which has important role and act as important target for therapeutic agents. Consequently, we used comparatively/ Homology modeling method to predict the 3D structure of GPR15 followed by the validation of the predicted structures by using Ramachandran Plot, Errat, Qmean and ProSA. An online server ProBiS was to predict the binding sites and ligands for them as showed similarities with other proteins binding site. Among the 22 ligands used for docking, UK-432,097 and 1,2-Dimyristoyl-Sn-Glycero-3-Phosphocholine showed best binding energy than other compounds. This shows that UK-432,097 and 1,2-Dimyristoyl-Sn-Glycero-3-Phosphocholine could be better for further bioassay. Using UK-432,097 and 1,2-Dimyristoyl-Sn-Glycero-3-Phosphocholine for structure based virtual screening could help...
Chemotherapy is extensively used for the treatment of various types of cancer. Multidrug resistan... more Chemotherapy is extensively used for the treatment of various types of cancer. Multidrug resistance (MDR) against chemotherapeutics agents remains one of the most important hurdle in the successful chemotherapy of cancer. The efflux mechanism of ABC transporters is considered as the primary cause of Multidrug resistance (MDR). CC10 (MRP7) is recently described as one of the new players in the development of MDR in cancer cells. Therefore, we used a computational approach to model the 3D structure of ABCC10 and used the already reported anti-cancerous compounds against the ligand binding site of ABCC10. In this work, we have developed homology models of the ABCC10 transporter and assessed them in virtual screening for the identification of novel ligands. The models were generated by MOE, MODELLER, I-TASSER, EXPASY, PHYRE2. Energy minimization was carried out by using YASARA energy minimization server. The final model was built by combining all these models using MODELLER. The binding...
The coastal geomorphology of the Raukumara Peninsula, North Island, New Zealand, is investigated ... more The coastal geomorphology of the Raukumara Peninsula, North Island, New Zealand, is investigated with the aim of understanding the geodynamics of this segment of the Hikurangi subduction zone. There are few active faults on the Raukumara Peninsula and there have been no historical subduction earthquakes on this part of the margin. Geodetic and geologic evidence suggests the onshore forearc is extending and sliding trenchward. However, Holocene and Pleistocene terraces that have some of the highest uplift rates and elevation in New Zealand occur in this region. Sediment underplating has previously been suggested as a cause of coastal forearc uplift, yet the inferred gradualness of this process does not reconcile with the inferred episodic nature of uplift suggested by stepped Holocene marine terraces along the Raukumara Peninsula. This study focuses on resolving these apparent inconsistencies in the current knowledge of the Raukumara sector of the Hikurangi margin by using the mechan...
Interdisciplinary Sciences: Computational Life Sciences, 2020
Most recently, an outbreak of severe pneumonia caused by the infection of SARS-CoV-2, a novel cor... more Most recently, an outbreak of severe pneumonia caused by the infection of SARS-CoV-2, a novel coronavirus first identified in Wuhan, China, imposes serious threats to public health. Upon infecting host cells, coronaviruses assemble a multi-subunit RNA-synthesis complex of viral non-structural proteins (nsp) responsible for the replication and transcription of the viral genome. Therefore, the role and inhibition of nsp12 are indispensable. A cryo-EM structure of RdRp from SARs-CoV-2 was used to identify novel drugs from Northern South African medicinal compounds database (NANPDB) by using computational virtual screening and molecular docking approaches. Considering Remdesivir as the control, 42 compounds were shortlisted to have docking score better than Remdesivir. The top 5 hits were validated by using molecular dynamics simulation approach and free energy calculations possess strong inhibitory properties than the Remdesivir. Thus, this study paved a way for designing novel drugs by decoding the architecture of an important enzyme and its inhibition with compounds from natural resources. This disclosing of necessary knowledge regarding the screening and the identification of top hits could help to design effective therapeutic candidates against the coronaviruses and design robust preventive measurements.
Journal of Biomolecular Structure and Dynamics, 2020
The current coronavirus (SARS-COV-2) pandemic and phenomenal spread to every nook and cranny of t... more The current coronavirus (SARS-COV-2) pandemic and phenomenal spread to every nook and cranny of the world has raised major apprehensions about the modern public health care system. So far as a result of this epidemic, 4,434,653 confirmed cases and 302,169 deaths are reported. The growing infection rate and death toll demand the use of all possible approaches to design novel drugs and vaccines to curb this disease. In this study, we combined drugs repurposing and virtual drug screening strategies to target 3CLpro, which has an essential role in viral maturation and replication. A total of 31 FDA approved anti-HIV drugs, and Traditional Chinese medicines (TCM) database were screened to find potential inhibitors. As a result, Saquinavir, and five drugs (TCM5280805, TCM5280445, TCM5280343, TCM5280863, and TCM5458190) from the TCM database were found as promising hits. Furthermore, results from molecular dynamics simulation and total binding free energy revealed that Saquinavir and TCM5280805 target the catalytic dyad (His41 and Cys145) and possess stable dynamics behavior. Thus, we suggest that these compounds should be tested experimentally against the SARS-COV-2 as Saquinavir has been reported to inhibit HIV protease experimentally. Considering the intensity of coronavirus dissemination, the present research is in line with the idea of discovering the latest inhibitors against the coronavirus essential pathways to accelerate the drug development cycle.
This paper focuses on parametric model order reduction (PMOR) of guided ultrasonic wave propagati... more This paper focuses on parametric model order reduction (PMOR) of guided ultrasonic wave propagation and its interaction with damage in a fiber metal laminate (FML). Structural health monitoring in FML seeks to detect, localize and characterize the damage with high accuracy and minimal use of sensors. This can be achieved by the inverse problem analysis approach which employs the signal measurement data recorded by the embedded sensors in the structure. The inverse analysis requires to solve the forward simulation of the underlying system several thousand times. These simulations are often exorbitantly expensive and triggered the need for improving their computational efficiency. A PMOR approach hinged on the proper orthogonal decomposition method is presented in this paper. An adaptive parameter sampling technique is established with the aid of a surrogate model to efficiently update the reduced-order basis in a greedy fashion. A numerical experiment is conducted to illustrate the p...
Supraventricular tachycardia (SVT) refers to the narrow complex tachycardia originating at or abo... more Supraventricular tachycardia (SVT) refers to the narrow complex tachycardia originating at or above the bundle of His. Several risk factors are associated with the development and recurrence of SVT, but its association with gastric problems, especially dyspepsia, is relatively rare. We report the case of a 54-yearold female who presented to the emergency room (ER) with palpitations, which were diagnosed as an episode of paroxysmal supraventricular tachycardia (PSVT). She had a history of PSVT in the past, along with hypertension and dyspepsia. After thorough history and examination, dyspepsia was identified as the common trigger of her PSVT episodes, pointing towards the likelihood of gastrocardiac symptoms. Therefore, an appropriate regimen of beta-blockers, proton pump inhibitors (PPIs), and anti-foaming agents (simethicone) was prescribed to manage her symptoms with the plan to perform a catheter ablation later.
To the Editor, The recent SARs-CoV-2 created focal news when the paradoxical spread was reported ... more To the Editor, The recent SARs-CoV-2 created focal news when the paradoxical spread was reported in the Wuhan province of China, further jeopardizing the existence of the human race on the planet earth. Due to its rapid expansion throughout the world, the COVID-19 outbreak was declared as a global pandemic by the World Health Organization (WHO) on March 20, 2020. The updates of November 13, 2020, have been reported 53,429,139 infections and 1,304,470 deaths. Fever, shortness of breath, coughing, myalgia, dyspnea, and radiological indications of ground-glass lung opacity compatible with atypical pneumonia are the signs exhibited by most patients with COVID-19. However, some patients have also been reported to have asymptomatic or mildly symptomatic (Chen et al., 2020; Huang et al., 2020; Lu et al., 2020). The whole proteome of the SARS-CoV-2 is encoded by ~30 kb a genome. The whole-genome encodes three major components, including non-structural (NS), structural, and accessory proteins (Durojaiye, Clarke, Stamatiades, & Wang, 2020). The genes found on the 30-terminus encode the four structural proteins constituting the main envelope of the virus and eight accessory proteins. Among the structural proteins small envelope protein (E), spike surface glycoprotein (S), nucleocapsid protein (N), and the membrane protein (M) while the eight accessory proteins codes for 3a, 3b, p6, 7a, 7b, 8b, 9b and ORF14 (Wu et al., 2020). In contrast, the two overlapping genes, ORFIa and ORF1ab, encode the non-structural proteins (polypeptides pp1a and pp1ab) and form a replication/transcription complex (RTC). These pp1a and pp1ab polypeptides are translated and then proteolytically cleaved by two main viral proteases, (papain-like protease) PLpro and (3-chymotrypsin-like protease) 3CLpro or main proteases (Mpro) (Perlman & Netland, 2009). PLpro is accountable for the cleavage of non-structural proteins (nsp 1–3). In contrast, the 3CLpro (Figure 1A) cleaves the polyprotein at 11 discrete sites downstream of nsp4 to yield different non-structural proteins that play a crucial role in the viral life cycle. Previous studies have indicated that 3CLpro (Mpro) plays an important role in cell proliferation and maturation. So, the inhibition of this target would significantly contribute to controlling the COVID-19 (Needle, Lountos, & Waugh, 2015). Because of these multi-faceted aspects, 3CLpro has been deemed as a promising drug development target for anti-coronaviruses (Hatada et al., 2020). In this study, we have used both in silico and in vitro approaches to confirm the activity of an active compound Kaempferol (Figure 1B), which was reported in our previous study to potentially interact with the SARs-CoV-2 main protease 3CLpro (Khan et al., 2020). The compound found through molecular search from the Traditional Chinese Medicine (TCM) was re-docked here against the active site of the main protease. AutoDock Vina (Trott & Olson, 2010) with exhaustiveness set as 64 was used to dock kaempferol against the main protease (3CLpro). The docking predictions revealed the docking scores for the 10 conformations. Among the 10 conformations, the docking score for the first three conformations was −6.4 kcal/mol. Previously, these residues His41, Met49, Tyr54, Phe140, Leu141, Asn142, Cys145, His163, Met165, Glu166, Leu167, Phe185, Asn187, Arg188, and Gln192 comprised the active site. Therefore, the first three conformations were analyzed for potential interactions with these residues. Conformation 1 (Figure 1C) formed six hydrogen bonds with the active site residues, including Phe140, Leu141, Asn142, His163, Glu166, and Arg188. A pie-sulfur interaction was formed by Cys145, while the Met165 formed a pie-alkyl interaction. The second conformation (Figure 1D) with the docking score (−6.4 kcal/mol) also formed six hydrogen bonds with the key active site residues. Among the key interactions, five were formed with Phe140, Leu141, Asn142, and Cys145, while one hydrogen bond was formed with Arg188. The conformation 3 formed only three hydrogen bonds with the key residues. As shown in (Figure 1E) Met49, Phe140, and His163 are involved in the interaction with Kaempferol. Hence, the docking predictions significantly confirm that kaempferol potentially interacts with the same active site residue even in different conformations, thus verify its activity against the 3CLpro. To further validate the potential of kaempferol as an active drug, a biophysical investigation was performed. Using Amber20 (SalomonFerrer, Case, & Walker, 2013), a 250 ns simulation for each conformation was performed to reveal the dynamic behavior of Kaempferol-3CLpro complexes. The parameters were set as used in the previous study (Khan et al., 2020). To demonstrate the structural stability of the complexes, root mean square deviation (RMSD) of each complex was calculated. As given in Figure 1F–H, all the complexes reached the stability at 1.8 Å and reached the equilibrium state at 15 ns.…
Pirin (PIR) protein is highly conserved in both prokaryotic and eukaryotic organisms. Recently, i... more Pirin (PIR) protein is highly conserved in both prokaryotic and eukaryotic organisms. Recently, it has been identified that PIR positively regulates breast cancer cell proliferation, xenograft tumor formation, and metastasis, through an enforced transition of G1/S phase of the cell cycle by upregulation of E2F1 expression at the transcriptional level. Keeping in view the importance of PIR in many crucial cellular processes in humans, we used a variety of computational tools to identify non-synonymous single-nucleotide polymorphisms (SNPs) in the PIR gene that are highly deleterious for the structure and function of PIR protein. Out of 173 SNPs identified in the protein, 119 are non-synonymous, and by consensus, 24 mutations were confirmed to be deleterious in nature. Mutations such as V257A, I28T, and I264S were unveiled as highly destabilizing due to a significant stability fold change on the protein structure. This observation was further established through molecular dynamics (MD...
The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome c... more The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading fast worldwide. There is a pressing need to understand how the virus counteracts host innate immune responses. Deleterious clinical manifestations of coronaviruses have been associated with virus-induced direct dysregulation of innate immune responses occurring via viral macrodomains located within nonstructural protein-3 (Nsp3). However, no substantial information is available concerning the relationship of macrodomains to the unusually high pathogenicity of SARS-CoV-2. Here, we show that structural evolution of macrodomains may impart a critical role to the unique pathogenicity of SARS-CoV-2. Using sequence, structural, and phylogenetic analysis, we identify a specific set of historical substitutions that recapitulate the evolution of the macrodomains that counteract host immune response. These evolutionary substitutions may alter and reposition t...
Computational and Structural Biotechnology Journal, 2020
The emergence of recent SARS-CoV-2 has become a global health issue. This single-stranded positiv... more The emergence of recent SARS-CoV-2 has become a global health issue. This single-stranded positivesense RNA virus is continuously spreading with increasing morbidities and mortalities. The proteome of this virus contains four structural and sixteen nonstructural proteins that ensure the replication of the virus in the host cell. However, the role of phosphoprotein (N) in RNA recognition, replicating, transcribing the viral genome, and modulating the host immune response is indispensable. Recently, the NMR structure of the N-terminal domain of the Nucleocapsid Phosphoprotein has been reported, but its precise structural mechanism of how the ssRNA interacts with it is not reported yet. Therefore, here, we have used an integrated computational pipeline to identify the key residues, which play an essential role in RNA recognition. We generated multiple variants by using an alanine scanning strategy and performed an extensive simulation for each system to signify the role of each interfacial residue. Our analyses suggest that residues T57A, H59A, S105A, R107A, F171A, and Y172A significantly affected the dynamics and binding of RNA. Furthermore, per-residue energy decomposition analysis suggests that residues T57, H59, S105 and R107 are the key hotspots for drug discovery. Thus, these residues may be useful as potential pharmacophores in drug designing.
Reports of the novel and more contagious strains of SARS-CoV-2 originated in different countries ... more Reports of the novel and more contagious strains of SARS-CoV-2 originated in different countries have further aggravated the pandemic situation. The recent substitutions in spike protein may be critical for the virus to evade the host’s immune system and therapeutics that have already been developed. Thus, this study has employed an immunoinformatics pipeline to target the spike protein of this novel strain to construct an immunogenic epitope (CTL, HTL, and B cell) vaccine against the new variant. Our investigation revealed that 12 different epitopes imparted a critical role in immune response induction. This was validated by an exploration of physiochemical properties and experimental feasibility. In silico and host immune simulation confirmed the expression and induction of both primary and secondary immune factors such as IL, cytokines, and antibodies. The current study warrants further lab experiments to demonstrate its efficacy and safety.
Journal of Biomolecular Structure and Dynamics, 2020
Hepatitis C virus (HCV), which infected 71 million worldwide and about 5%-6% are from Pakistan, i... more Hepatitis C virus (HCV), which infected 71 million worldwide and about 5%-6% are from Pakistan, is an ssRNA virus, responsible for end-stage liver disease. To date, no effective therapy is available to cure this disease. Hence, it is important to study the most prevalent genotypes infecting human population and design novel vaccine or small molecule inhibitors to control the infections associated with HCV. Therefore, in this study clinical samples (n = 35; HCV-3a) from HCV patients were subjected to Sanger sequencing method. The sequencing of the core gene, which is generally considered as conserved, involved in the detection, quantitation and genotyping of HCV was performed. Multiple mutations, that is, R46C, R70Q, L91C, G60E, N/S105A, P108A, N110I, S116V, G90S, A77G and G145R that could be linked with response to antiviral therapies were detected. Phylogenetic analysis suggests emerging viral isolates are circulating in Pakistan. Using ab initio modelling technique, we predicted the 3D structure of core protein and subjected to molecular dynamics simulation to extract the most stable conformation of the structure for further analysis. Immunoinformatic approaches were used to propose a multi-epitopes vaccine against HCV by using core protein. The vaccine constructs consist of nine CTL and three HTL epitopes joined by different linkers were docked against the two reported Toll-like receptors (TLR-3 and TLR-8). Docking of vaccine construct with TLR-3 and TLR-8 shows proper binding and in silico expression of the vaccine resulted in a CAI value of 0.93. These analyses suggest that specific immune responses may be produced by the proposed vaccine. Communicated by Ramaswamy H. Sarma.
Journal of Biomolecular Structure and Dynamics, 2020
Abstract Porphyromonas gingivalis, a prominent pathogen responsible for acute periodontal disease... more Abstract Porphyromonas gingivalis, a prominent pathogen responsible for acute periodontal diseases, is widely studied by the scientific community for its successful evasion of the host immune system. P. gingivalis is associated with rheumatoid arthritis, dementia, and Alzheimer's. The pathogen successfully survives itself against the heavy load of conventional antibiotics because of its ability to evade the host immune system. Subtractive proteomics and reverse vaccinology approaches were employed in order to prioritize the best proteins for vaccine designing. Three vaccine candidates with Uniprot ID: Q7MWZ2 (histidine Kinase), Q7MVL1 (Fe (2+) transporter), and Q7MWZ2 (Capsular polysaccharide transport protein) were identified for vaccine designing. These proteins are antigenic and essential for pathogen survival. A wide range of immunoinformatics tools was applied for the prediction of epitopes, B, and T cells, for the vaccine candidate proteins. Molecular docking of the predicted epitopes against the MHC molecules were carried out. In-silico vaccine was constructed using carefully evaluated epitopes and consequently modeled for docking with human Toll-like receptor 2. Chain C of Pam3CSK4 (PDB ID; 2Z7X) was linked to the vaccine as an adjuvant to boost immune response towards the vaccine. For stability evaluation of the vaccine-TLR-2 docked complex, Molecular Dynamics simulations were performed. The reverse-translated nucleotide sequence cloned in Eschericia coli to attain the maximal expression of the vaccine protein. The maximal expression was ensured by CAI score of 0.96. The current vaccine requires future experimental validation to confirm its effectiveness. The vaccine developed will be helpful to protect against P. gingivalis associated infections. Communicated by Ramaswamy H. Sarma
The purpose of this paper is to explain how young firms in an emerging market create sustainable ... more The purpose of this paper is to explain how young firms in an emerging market create sustainable competitive advantage through innovation. The study through the Resource-Based View theory examines the effect of innovation practices on sustainable competitive advantage of young firms in Vietnam. Data were collected from 289 young firms in Vietnam. PLS SEM using Smart PLS 3.0 software were used to analyze and examine the hypotheses. The results indicated that three direct effects between innovation practices which are strategy innovation, process innovation, system innovation and sustainable competitive advantage were significant while the effect of organization innovation and technology innovation on sustainable competitive advantage were not significant in this study. This finding not only created important empirical evidence contributing to the current stock of knowledge but also opens up the important direction for young firms who are striving to achieve sustainable competitive advantage in the current context.
Niemann-Pick disease (NPD) type A is a fatal autosomal recessive lysosomal storage disorder. This... more Niemann-Pick disease (NPD) type A is a fatal autosomal recessive lysosomal storage disorder. This rare condition impairs the metabolization of lipids, leading to their accumulation within the cells. Consequently, it causes growth retardation, pancytopenia, and cellular malfunctioning in various organ systems, including ocular, hepatic, pulmonary, brain, and neuronal tissues. Although rare, these patients present in both emergency and outpatient settings. Here, we report the case of a seven-month-old male infant who presented to the emergency department with continuous fever for one week, poor feeding, and failure to thrive. After a thorough history, examination, and laboratory workup, NPD type A was diagnosed. The patient received symptomatic therapy with the continuation of conservative management. In addition, the parents received detailed counseling regarding the genetics, progressive disease course, and prognosis of this condition.
Most recently, an outbreak of severe pneumonia caused by the infection of 2019-nCoV, a novel coro... more Most recently, an outbreak of severe pneumonia caused by the infection of 2019-nCoV, a novel coronavirus first identified in Wuhan, China, imposes serious threats to public health. Upon infecting host cells, coronaviruses assemble a multi-subunit RNA-synthesis complex of viral non-structural proteins (nsp) responsible for the replication and transcription of the viral genome. Therefore, the role and inhibition of nsp12 are indispensable. Since there is no crystallographic structure of RdRp is available, so, here, we present the 3-dimensional structure of the 2019-nCoV nsp12 polymerase using a computational approach. nsp12 of 2019-nCoV possesses an architecture common to all viral polymerases as well as a large N-terminal extension. This structure illuminates the assembly of the coronavirus core RNA-synthesis machinery, provides key insights into nsp12 polymerase catalysis and fidelity, and acts as a template for the design of novel antiviral therapeutics. Besides, the experimental s...
Here we reported recent advancement in the 3D structures of G protein-coupled receptors (GPCR) wh... more Here we reported recent advancement in the 3D structures of G protein-coupled receptors (GPCR) which act as major receptors in the spread of many diseases like HIV-1 and HIV-2. GPR15 is one among the GPCRs which has important role and act as important target for therapeutic agents. Consequently, we used comparatively/ Homology modeling method to predict the 3D structure of GPR15 followed by the validation of the predicted structures by using Ramachandran Plot, Errat, Qmean and ProSA. An online server ProBiS was to predict the binding sites and ligands for them as showed similarities with other proteins binding site. Among the 22 ligands used for docking, UK-432,097 and 1,2-Dimyristoyl-Sn-Glycero-3-Phosphocholine showed best binding energy than other compounds. This shows that UK-432,097 and 1,2-Dimyristoyl-Sn-Glycero-3-Phosphocholine could be better for further bioassay. Using UK-432,097 and 1,2-Dimyristoyl-Sn-Glycero-3-Phosphocholine for structure based virtual screening could help...
Chemotherapy is extensively used for the treatment of various types of cancer. Multidrug resistan... more Chemotherapy is extensively used for the treatment of various types of cancer. Multidrug resistance (MDR) against chemotherapeutics agents remains one of the most important hurdle in the successful chemotherapy of cancer. The efflux mechanism of ABC transporters is considered as the primary cause of Multidrug resistance (MDR). CC10 (MRP7) is recently described as one of the new players in the development of MDR in cancer cells. Therefore, we used a computational approach to model the 3D structure of ABCC10 and used the already reported anti-cancerous compounds against the ligand binding site of ABCC10. In this work, we have developed homology models of the ABCC10 transporter and assessed them in virtual screening for the identification of novel ligands. The models were generated by MOE, MODELLER, I-TASSER, EXPASY, PHYRE2. Energy minimization was carried out by using YASARA energy minimization server. The final model was built by combining all these models using MODELLER. The binding...
The coastal geomorphology of the Raukumara Peninsula, North Island, New Zealand, is investigated ... more The coastal geomorphology of the Raukumara Peninsula, North Island, New Zealand, is investigated with the aim of understanding the geodynamics of this segment of the Hikurangi subduction zone. There are few active faults on the Raukumara Peninsula and there have been no historical subduction earthquakes on this part of the margin. Geodetic and geologic evidence suggests the onshore forearc is extending and sliding trenchward. However, Holocene and Pleistocene terraces that have some of the highest uplift rates and elevation in New Zealand occur in this region. Sediment underplating has previously been suggested as a cause of coastal forearc uplift, yet the inferred gradualness of this process does not reconcile with the inferred episodic nature of uplift suggested by stepped Holocene marine terraces along the Raukumara Peninsula. This study focuses on resolving these apparent inconsistencies in the current knowledge of the Raukumara sector of the Hikurangi margin by using the mechan...
Interdisciplinary Sciences: Computational Life Sciences, 2020
Most recently, an outbreak of severe pneumonia caused by the infection of SARS-CoV-2, a novel cor... more Most recently, an outbreak of severe pneumonia caused by the infection of SARS-CoV-2, a novel coronavirus first identified in Wuhan, China, imposes serious threats to public health. Upon infecting host cells, coronaviruses assemble a multi-subunit RNA-synthesis complex of viral non-structural proteins (nsp) responsible for the replication and transcription of the viral genome. Therefore, the role and inhibition of nsp12 are indispensable. A cryo-EM structure of RdRp from SARs-CoV-2 was used to identify novel drugs from Northern South African medicinal compounds database (NANPDB) by using computational virtual screening and molecular docking approaches. Considering Remdesivir as the control, 42 compounds were shortlisted to have docking score better than Remdesivir. The top 5 hits were validated by using molecular dynamics simulation approach and free energy calculations possess strong inhibitory properties than the Remdesivir. Thus, this study paved a way for designing novel drugs by decoding the architecture of an important enzyme and its inhibition with compounds from natural resources. This disclosing of necessary knowledge regarding the screening and the identification of top hits could help to design effective therapeutic candidates against the coronaviruses and design robust preventive measurements.
Journal of Biomolecular Structure and Dynamics, 2020
The current coronavirus (SARS-COV-2) pandemic and phenomenal spread to every nook and cranny of t... more The current coronavirus (SARS-COV-2) pandemic and phenomenal spread to every nook and cranny of the world has raised major apprehensions about the modern public health care system. So far as a result of this epidemic, 4,434,653 confirmed cases and 302,169 deaths are reported. The growing infection rate and death toll demand the use of all possible approaches to design novel drugs and vaccines to curb this disease. In this study, we combined drugs repurposing and virtual drug screening strategies to target 3CLpro, which has an essential role in viral maturation and replication. A total of 31 FDA approved anti-HIV drugs, and Traditional Chinese medicines (TCM) database were screened to find potential inhibitors. As a result, Saquinavir, and five drugs (TCM5280805, TCM5280445, TCM5280343, TCM5280863, and TCM5458190) from the TCM database were found as promising hits. Furthermore, results from molecular dynamics simulation and total binding free energy revealed that Saquinavir and TCM5280805 target the catalytic dyad (His41 and Cys145) and possess stable dynamics behavior. Thus, we suggest that these compounds should be tested experimentally against the SARS-COV-2 as Saquinavir has been reported to inhibit HIV protease experimentally. Considering the intensity of coronavirus dissemination, the present research is in line with the idea of discovering the latest inhibitors against the coronavirus essential pathways to accelerate the drug development cycle.
This paper focuses on parametric model order reduction (PMOR) of guided ultrasonic wave propagati... more This paper focuses on parametric model order reduction (PMOR) of guided ultrasonic wave propagation and its interaction with damage in a fiber metal laminate (FML). Structural health monitoring in FML seeks to detect, localize and characterize the damage with high accuracy and minimal use of sensors. This can be achieved by the inverse problem analysis approach which employs the signal measurement data recorded by the embedded sensors in the structure. The inverse analysis requires to solve the forward simulation of the underlying system several thousand times. These simulations are often exorbitantly expensive and triggered the need for improving their computational efficiency. A PMOR approach hinged on the proper orthogonal decomposition method is presented in this paper. An adaptive parameter sampling technique is established with the aid of a surrogate model to efficiently update the reduced-order basis in a greedy fashion. A numerical experiment is conducted to illustrate the p...
Supraventricular tachycardia (SVT) refers to the narrow complex tachycardia originating at or abo... more Supraventricular tachycardia (SVT) refers to the narrow complex tachycardia originating at or above the bundle of His. Several risk factors are associated with the development and recurrence of SVT, but its association with gastric problems, especially dyspepsia, is relatively rare. We report the case of a 54-yearold female who presented to the emergency room (ER) with palpitations, which were diagnosed as an episode of paroxysmal supraventricular tachycardia (PSVT). She had a history of PSVT in the past, along with hypertension and dyspepsia. After thorough history and examination, dyspepsia was identified as the common trigger of her PSVT episodes, pointing towards the likelihood of gastrocardiac symptoms. Therefore, an appropriate regimen of beta-blockers, proton pump inhibitors (PPIs), and anti-foaming agents (simethicone) was prescribed to manage her symptoms with the plan to perform a catheter ablation later.
To the Editor, The recent SARs-CoV-2 created focal news when the paradoxical spread was reported ... more To the Editor, The recent SARs-CoV-2 created focal news when the paradoxical spread was reported in the Wuhan province of China, further jeopardizing the existence of the human race on the planet earth. Due to its rapid expansion throughout the world, the COVID-19 outbreak was declared as a global pandemic by the World Health Organization (WHO) on March 20, 2020. The updates of November 13, 2020, have been reported 53,429,139 infections and 1,304,470 deaths. Fever, shortness of breath, coughing, myalgia, dyspnea, and radiological indications of ground-glass lung opacity compatible with atypical pneumonia are the signs exhibited by most patients with COVID-19. However, some patients have also been reported to have asymptomatic or mildly symptomatic (Chen et al., 2020; Huang et al., 2020; Lu et al., 2020). The whole proteome of the SARS-CoV-2 is encoded by ~30 kb a genome. The whole-genome encodes three major components, including non-structural (NS), structural, and accessory proteins (Durojaiye, Clarke, Stamatiades, & Wang, 2020). The genes found on the 30-terminus encode the four structural proteins constituting the main envelope of the virus and eight accessory proteins. Among the structural proteins small envelope protein (E), spike surface glycoprotein (S), nucleocapsid protein (N), and the membrane protein (M) while the eight accessory proteins codes for 3a, 3b, p6, 7a, 7b, 8b, 9b and ORF14 (Wu et al., 2020). In contrast, the two overlapping genes, ORFIa and ORF1ab, encode the non-structural proteins (polypeptides pp1a and pp1ab) and form a replication/transcription complex (RTC). These pp1a and pp1ab polypeptides are translated and then proteolytically cleaved by two main viral proteases, (papain-like protease) PLpro and (3-chymotrypsin-like protease) 3CLpro or main proteases (Mpro) (Perlman & Netland, 2009). PLpro is accountable for the cleavage of non-structural proteins (nsp 1–3). In contrast, the 3CLpro (Figure 1A) cleaves the polyprotein at 11 discrete sites downstream of nsp4 to yield different non-structural proteins that play a crucial role in the viral life cycle. Previous studies have indicated that 3CLpro (Mpro) plays an important role in cell proliferation and maturation. So, the inhibition of this target would significantly contribute to controlling the COVID-19 (Needle, Lountos, & Waugh, 2015). Because of these multi-faceted aspects, 3CLpro has been deemed as a promising drug development target for anti-coronaviruses (Hatada et al., 2020). In this study, we have used both in silico and in vitro approaches to confirm the activity of an active compound Kaempferol (Figure 1B), which was reported in our previous study to potentially interact with the SARs-CoV-2 main protease 3CLpro (Khan et al., 2020). The compound found through molecular search from the Traditional Chinese Medicine (TCM) was re-docked here against the active site of the main protease. AutoDock Vina (Trott & Olson, 2010) with exhaustiveness set as 64 was used to dock kaempferol against the main protease (3CLpro). The docking predictions revealed the docking scores for the 10 conformations. Among the 10 conformations, the docking score for the first three conformations was −6.4 kcal/mol. Previously, these residues His41, Met49, Tyr54, Phe140, Leu141, Asn142, Cys145, His163, Met165, Glu166, Leu167, Phe185, Asn187, Arg188, and Gln192 comprised the active site. Therefore, the first three conformations were analyzed for potential interactions with these residues. Conformation 1 (Figure 1C) formed six hydrogen bonds with the active site residues, including Phe140, Leu141, Asn142, His163, Glu166, and Arg188. A pie-sulfur interaction was formed by Cys145, while the Met165 formed a pie-alkyl interaction. The second conformation (Figure 1D) with the docking score (−6.4 kcal/mol) also formed six hydrogen bonds with the key active site residues. Among the key interactions, five were formed with Phe140, Leu141, Asn142, and Cys145, while one hydrogen bond was formed with Arg188. The conformation 3 formed only three hydrogen bonds with the key residues. As shown in (Figure 1E) Met49, Phe140, and His163 are involved in the interaction with Kaempferol. Hence, the docking predictions significantly confirm that kaempferol potentially interacts with the same active site residue even in different conformations, thus verify its activity against the 3CLpro. To further validate the potential of kaempferol as an active drug, a biophysical investigation was performed. Using Amber20 (SalomonFerrer, Case, & Walker, 2013), a 250 ns simulation for each conformation was performed to reveal the dynamic behavior of Kaempferol-3CLpro complexes. The parameters were set as used in the previous study (Khan et al., 2020). To demonstrate the structural stability of the complexes, root mean square deviation (RMSD) of each complex was calculated. As given in Figure 1F–H, all the complexes reached the stability at 1.8 Å and reached the equilibrium state at 15 ns.…
Pirin (PIR) protein is highly conserved in both prokaryotic and eukaryotic organisms. Recently, i... more Pirin (PIR) protein is highly conserved in both prokaryotic and eukaryotic organisms. Recently, it has been identified that PIR positively regulates breast cancer cell proliferation, xenograft tumor formation, and metastasis, through an enforced transition of G1/S phase of the cell cycle by upregulation of E2F1 expression at the transcriptional level. Keeping in view the importance of PIR in many crucial cellular processes in humans, we used a variety of computational tools to identify non-synonymous single-nucleotide polymorphisms (SNPs) in the PIR gene that are highly deleterious for the structure and function of PIR protein. Out of 173 SNPs identified in the protein, 119 are non-synonymous, and by consensus, 24 mutations were confirmed to be deleterious in nature. Mutations such as V257A, I28T, and I264S were unveiled as highly destabilizing due to a significant stability fold change on the protein structure. This observation was further established through molecular dynamics (MD...
The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome c... more The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading fast worldwide. There is a pressing need to understand how the virus counteracts host innate immune responses. Deleterious clinical manifestations of coronaviruses have been associated with virus-induced direct dysregulation of innate immune responses occurring via viral macrodomains located within nonstructural protein-3 (Nsp3). However, no substantial information is available concerning the relationship of macrodomains to the unusually high pathogenicity of SARS-CoV-2. Here, we show that structural evolution of macrodomains may impart a critical role to the unique pathogenicity of SARS-CoV-2. Using sequence, structural, and phylogenetic analysis, we identify a specific set of historical substitutions that recapitulate the evolution of the macrodomains that counteract host immune response. These evolutionary substitutions may alter and reposition t...
Computational and Structural Biotechnology Journal, 2020
The emergence of recent SARS-CoV-2 has become a global health issue. This single-stranded positiv... more The emergence of recent SARS-CoV-2 has become a global health issue. This single-stranded positivesense RNA virus is continuously spreading with increasing morbidities and mortalities. The proteome of this virus contains four structural and sixteen nonstructural proteins that ensure the replication of the virus in the host cell. However, the role of phosphoprotein (N) in RNA recognition, replicating, transcribing the viral genome, and modulating the host immune response is indispensable. Recently, the NMR structure of the N-terminal domain of the Nucleocapsid Phosphoprotein has been reported, but its precise structural mechanism of how the ssRNA interacts with it is not reported yet. Therefore, here, we have used an integrated computational pipeline to identify the key residues, which play an essential role in RNA recognition. We generated multiple variants by using an alanine scanning strategy and performed an extensive simulation for each system to signify the role of each interfacial residue. Our analyses suggest that residues T57A, H59A, S105A, R107A, F171A, and Y172A significantly affected the dynamics and binding of RNA. Furthermore, per-residue energy decomposition analysis suggests that residues T57, H59, S105 and R107 are the key hotspots for drug discovery. Thus, these residues may be useful as potential pharmacophores in drug designing.
Reports of the novel and more contagious strains of SARS-CoV-2 originated in different countries ... more Reports of the novel and more contagious strains of SARS-CoV-2 originated in different countries have further aggravated the pandemic situation. The recent substitutions in spike protein may be critical for the virus to evade the host’s immune system and therapeutics that have already been developed. Thus, this study has employed an immunoinformatics pipeline to target the spike protein of this novel strain to construct an immunogenic epitope (CTL, HTL, and B cell) vaccine against the new variant. Our investigation revealed that 12 different epitopes imparted a critical role in immune response induction. This was validated by an exploration of physiochemical properties and experimental feasibility. In silico and host immune simulation confirmed the expression and induction of both primary and secondary immune factors such as IL, cytokines, and antibodies. The current study warrants further lab experiments to demonstrate its efficacy and safety.
Journal of Biomolecular Structure and Dynamics, 2020
Hepatitis C virus (HCV), which infected 71 million worldwide and about 5%-6% are from Pakistan, i... more Hepatitis C virus (HCV), which infected 71 million worldwide and about 5%-6% are from Pakistan, is an ssRNA virus, responsible for end-stage liver disease. To date, no effective therapy is available to cure this disease. Hence, it is important to study the most prevalent genotypes infecting human population and design novel vaccine or small molecule inhibitors to control the infections associated with HCV. Therefore, in this study clinical samples (n = 35; HCV-3a) from HCV patients were subjected to Sanger sequencing method. The sequencing of the core gene, which is generally considered as conserved, involved in the detection, quantitation and genotyping of HCV was performed. Multiple mutations, that is, R46C, R70Q, L91C, G60E, N/S105A, P108A, N110I, S116V, G90S, A77G and G145R that could be linked with response to antiviral therapies were detected. Phylogenetic analysis suggests emerging viral isolates are circulating in Pakistan. Using ab initio modelling technique, we predicted the 3D structure of core protein and subjected to molecular dynamics simulation to extract the most stable conformation of the structure for further analysis. Immunoinformatic approaches were used to propose a multi-epitopes vaccine against HCV by using core protein. The vaccine constructs consist of nine CTL and three HTL epitopes joined by different linkers were docked against the two reported Toll-like receptors (TLR-3 and TLR-8). Docking of vaccine construct with TLR-3 and TLR-8 shows proper binding and in silico expression of the vaccine resulted in a CAI value of 0.93. These analyses suggest that specific immune responses may be produced by the proposed vaccine. Communicated by Ramaswamy H. Sarma.
Journal of Biomolecular Structure and Dynamics, 2020
Abstract Porphyromonas gingivalis, a prominent pathogen responsible for acute periodontal disease... more Abstract Porphyromonas gingivalis, a prominent pathogen responsible for acute periodontal diseases, is widely studied by the scientific community for its successful evasion of the host immune system. P. gingivalis is associated with rheumatoid arthritis, dementia, and Alzheimer's. The pathogen successfully survives itself against the heavy load of conventional antibiotics because of its ability to evade the host immune system. Subtractive proteomics and reverse vaccinology approaches were employed in order to prioritize the best proteins for vaccine designing. Three vaccine candidates with Uniprot ID: Q7MWZ2 (histidine Kinase), Q7MVL1 (Fe (2+) transporter), and Q7MWZ2 (Capsular polysaccharide transport protein) were identified for vaccine designing. These proteins are antigenic and essential for pathogen survival. A wide range of immunoinformatics tools was applied for the prediction of epitopes, B, and T cells, for the vaccine candidate proteins. Molecular docking of the predicted epitopes against the MHC molecules were carried out. In-silico vaccine was constructed using carefully evaluated epitopes and consequently modeled for docking with human Toll-like receptor 2. Chain C of Pam3CSK4 (PDB ID; 2Z7X) was linked to the vaccine as an adjuvant to boost immune response towards the vaccine. For stability evaluation of the vaccine-TLR-2 docked complex, Molecular Dynamics simulations were performed. The reverse-translated nucleotide sequence cloned in Eschericia coli to attain the maximal expression of the vaccine protein. The maximal expression was ensured by CAI score of 0.96. The current vaccine requires future experimental validation to confirm its effectiveness. The vaccine developed will be helpful to protect against P. gingivalis associated infections. Communicated by Ramaswamy H. Sarma
Uploads
Papers by Shoaib Saleem