Background: Laboratory tests for routine drug of abuse and toxicology (DOA/Tox) screening, often ... more Background: Laboratory tests for routine drug of abuse and toxicology (DOA/Tox) screening, often used in emergency medicine, generally utilize antibody-based tests (immunoassays) to detect classes of drugs such as amphetamines, barbiturates, benzodiazepines, opiates, and tricyclic antidepressants, or individual drugs such as cocaine, methadone, and phencyclidine. A key factor in assay sensitivity and specificity is the drugs or drug metabolites that were used as antigenic targets to generate the assay antibodies. All DOA/Tox screening immunoassays can be limited by false positives caused by cross-reactivity from structurally related compounds. For immunoassays targeted at a particular class of drugs, there can also be false negatives if there is failure to detect some drugs or their metabolites within that class.
Background-Immunoassays used for routine drug of abuse (DOA) and toxicology screening may be limi... more Background-Immunoassays used for routine drug of abuse (DOA) and toxicology screening may be limited by cross-reacting compounds able to bind to the antibodies in a manner similar to the target molecule(s). To date, there has been little systematic investigation using computational tools to predict cross-reactive compounds.
Exploration of triclosan analogs has led to novel diaryl ureas with significant potency against i... more Exploration of triclosan analogs has led to novel diaryl ureas with significant potency against in vitro cultures of drug-resistant and drug-sensitive strains of the human malaria parasite Plasmodium falciparum. Compound 18 demonstrated EC(50) values of 37 and 55 nM versus in vitro cultured parasite strains and promising in vivo efficacy in a Plasmodium berghei antimalarial mouse model, with >50% survival at day 31 post-treatment when administered subcutaneously at 256 mg/kg. This series of compounds provides a chemical scaffold of novel architecture, as validated by cheminformatics analysis, to pursue antimalarial drug discovery efforts.
Drug Efficacy, Safety, and Biologics Discovery, 2008
... The development of systems biology models in the pharmaceutical industry relies onknowledge o... more ... The development of systems biology models in the pharmaceutical industry relies onknowledge of drug targets in their biological context that has been codified and assembled from prior research studies reported in the literature. Page 14. ...
This article will highlight how traditional drug discovery is shifting towards integration of web... more This article will highlight how traditional drug discovery is shifting towards integration of web-based databases and tools. This integration is facilitating true online networked drug discovery collaborations -linking collaborators with both data and data analysis tools in a common platform. We will describe current notable efforts in this area and some of the key databases that are being used as resources for the collaborations. In particular, we discuss databases that are relevant to emerging discovery strategies, databases linking molecules, target and biological pathway data, databases that classify targets by drug action and databases that bridge to the growing pool of genomic data, such as the phenotype profiling of currently marketed drugs. These online efforts are innovative and accessible, and are able to expand the networks of research collaborators so they are able to contribute significantly to drug discovery projects, both locally and globally.
Page 1. 15 NOVEL APPLICATIONS OF KERNEL–PARTIAL LEAST SQUARES TO MODELING A COMPREHENSIVE ARRAY O... more Page 1. 15 NOVEL APPLICATIONS OF KERNEL–PARTIAL LEAST SQUARES TO MODELING A COMPREHENSIVE ARRAY OF PROPERTIES FOR DRUG DISCOVERY Sean Ekins, Mark J. Embrechts, Curt M. Breneman, Kam Jim, and Jean-Pierre Wery ...
Quantitative structure-activity relationship (QSAR) models have been developed for a dataset of 3... more Quantitative structure-activity relationship (QSAR) models have been developed for a dataset of 3133 compounds defined as either active or inactive against P. falciparum. Since the dataset was strongly biased towards inactive compounds, different sampling approaches were employed to balance the ratio of actives vs. inactives, and models were rigorously validated using both internal and external validation approaches. The balanced accuracy for assessing the antimalarial activities of 70 external compounds was between 87% and 100% depending on the approach used to balance the dataset. Virtual screening of the ChemBridge database using QSAR models identified 176 putative antimalarial compounds that were submitted for experimental validation, along with 42 putative inactives as negative controls. Twenty five (14.2%) computational hits were found to have antimalarial activities with minimal cytotoxicity to mammalian cells, while all 42 putative inactives were confirmed experimentally. Structural inspection of confirmed active hits revealed novel chemical scaffolds, which could be employed as starting points to discover novel antimalarial agents.
Integrated computational approaches for Mycobacterium tuberculosis (Mtb) are useful to identify n... more Integrated computational approaches for Mycobacterium tuberculosis (Mtb) are useful to identify new molecules that could lead to future tuberculosis (TB) drugs. Our approach uses information derived from the TBCyc pathway and genome database, the Collaborative Drug Discovery TB database combined with 3D pharmacophores and dual event Bayesian models of whole-cell activity and lack of cytotoxicity. We have prioritized a large number of molecules that may act as mimics of substrates and metabolites in the TB metabolome. We computationally searched over 200,000 commercial molecules using 66 pharmacophores based on substrates and metabolites from Mtb and further filtering with Bayesian models. We ultimately tested 110 compounds in vitro that resulted in two compounds of interest, BAS 04912643 and BAS 00623753 (MIC of 2.5 and 5 μg/mL, respectively). These molecules were used as a starting point for hit-to-lead optimization. The most promising class proved to be the quinoxaline di-N-oxides, evidenced by transcriptional profiling to induce mRNA level perturbations most closely resembling known protonophores. One of these, SRI58 exhibited an MIC = 1.25 μg/mL versus Mtb and a CC50 in Vero cells of >40 μg/mL, while featuring fair Caco-2 A-B permeability (2.3 x 10-6 cm/s), kinetic solubility (125 μM at pH 7.4 in PBS) and mouse metabolic stability (63.6% remaining after 1 h incubation with mouse liver microsomes). Despite demonstration of how a combined bioinformatics/cheminformatics approach afforded a small molecule with promising in vitro profiles, we found that SRI58 did not exhibit quantifiable blood levels in mice.
... A Case Study Sándor Szalma Collaboration in Cancer Research Community: Cancer Biomedical Info... more ... A Case Study Sándor Szalma Collaboration in Cancer Research Community: Cancer Biomedical Informatics Grid (caBIG) George A. Komatsoulis ... 24. Open Source Drug Discovery Model Anshu Bhardwaj, Vinod Scaria, Zakir Thomas, Santhosh Adayikkoth, Open Source Drug ...
Wikipedia has become the world’s most famous encyclopedia using as it’s platform the MediaWiki op... more Wikipedia has become the world’s most famous encyclopedia using as it’s platform the MediaWiki open source software. The software is supported not only by the MediaWiki foundation but by a community of developers who build widgets and add-ons to extend the capabilities. This presentation will review how MediaWiki has been used as a container for a number of resources of value to chemists, specifically SciMobileApps, SciDBs and ScientistsDB holding content regarding mobile scientific apps, scientific databases and scientists. We will also review how chemistry content within Wikipedia has been used to enhance the content underlying the RSC ChemSpider database and how the platform supports an educational environment for chemistry students.
There is an overwhelming number of new resources for chemistry that would likely benefit both lib... more There is an overwhelming number of new resources for chemistry that would likely benefit both librarians and students in terms of improving access to data and information. While commercial solutions provided by an institution may be the primary resources there is now an enormous range of online tools, databases, resources, apps for mobile devices and, increasingly, wikis. This presentation will provide an overview of how wiki-based resources for scientists are developing and will introduce a number of developing wikis. These include wikis that are being used to teach chemistry to students as well as to source information about scientists, scientific databases and mobile apps.
The human pregnane X receptor (PXR) is a ligand dependent transcription factor that can be activa... more The human pregnane X receptor (PXR) is a ligand dependent transcription factor that can be activated by structurally diverse agonists including steroid hormones, bile acids, herbal drugs, and prescription medications. PXR regulates the transcription of several genes involved in xenobiotic detoxification and apoptosis. Activation of PXR has the potential to initiate adverse effects by altering drug pharmacokinetics or perturbing physiological processes. Hence, more reliable prediction of PXR activators would be valuable for pharmaceutical drug discovery to avoid potential toxic effects. Ligand- and protein structure-based computational models for PXR activation have been developed in several studies. There has been limited success with structure-based modeling approaches to predict human PXR activators, which can be attributed to the large and promiscuous site of this protein. Slightly better success has been achieved with ligand-based modeling methods including quantitative structure-activity relationship (QSAR) analysis, pharmacophore modeling and machine learning that use appropriate descriptors to account for the diversity of the ligand classes that bind to PXR. These combined computational approaches using molecular shape information may assist scientists to more confidently identify PXR activators. This chapter reviews the various ligand and structure based methods undertaken to date and their results.
Nuclear receptors (NRs) are important biological macromolecular transcription factors that are im... more Nuclear receptors (NRs) are important biological macromolecular transcription factors that are implicated in multiple biological pathways and may interact with other xenobiotics that are endocrine disruptors present in the environment. Examples of important NRs include the androgen receptor (AR), estrogen receptors (ER), and the pregnane X receptor (PXR). In this study we have utilized the Ligand Activity by Surface Similarity Order (LASSO) method, a ligand-based virtual screening strategy to derive structural (surface/shape) molecular features used to generate predictive models of biomolecular activity for AR, ER, and PXR. For PXR, twentyfive models were built using between 8 to 128 agonists and tested using 3000, 8000, and 24,000 drug-like decoys including PXR inactive compounds ( = 228). Preliminary studies with AR and ER using LASSO suggested the utility of this approach with 2-fold enrichment factors at 20%. We found that models with 64-128 PXR actives provided enrichment factors of 10-fold (10% actives in the top 1% of compounds screened). The LASSO models for AR and ER have been deployed and are freely available online, and they represent a ligand-based prediction method for putative NR activity of compounds in this database.
Background: Laboratory tests for routine drug of abuse and toxicology (DOA/Tox) screening, often ... more Background: Laboratory tests for routine drug of abuse and toxicology (DOA/Tox) screening, often used in emergency medicine, generally utilize antibody-based tests (immunoassays) to detect classes of drugs such as amphetamines, barbiturates, benzodiazepines, opiates, and tricyclic antidepressants, or individual drugs such as cocaine, methadone, and phencyclidine. A key factor in assay sensitivity and specificity is the drugs or drug metabolites that were used as antigenic targets to generate the assay antibodies. All DOA/Tox screening immunoassays can be limited by false positives caused by cross-reactivity from structurally related compounds. For immunoassays targeted at a particular class of drugs, there can also be false negatives if there is failure to detect some drugs or their metabolites within that class.
Background-Immunoassays used for routine drug of abuse (DOA) and toxicology screening may be limi... more Background-Immunoassays used for routine drug of abuse (DOA) and toxicology screening may be limited by cross-reacting compounds able to bind to the antibodies in a manner similar to the target molecule(s). To date, there has been little systematic investigation using computational tools to predict cross-reactive compounds.
Exploration of triclosan analogs has led to novel diaryl ureas with significant potency against i... more Exploration of triclosan analogs has led to novel diaryl ureas with significant potency against in vitro cultures of drug-resistant and drug-sensitive strains of the human malaria parasite Plasmodium falciparum. Compound 18 demonstrated EC(50) values of 37 and 55 nM versus in vitro cultured parasite strains and promising in vivo efficacy in a Plasmodium berghei antimalarial mouse model, with >50% survival at day 31 post-treatment when administered subcutaneously at 256 mg/kg. This series of compounds provides a chemical scaffold of novel architecture, as validated by cheminformatics analysis, to pursue antimalarial drug discovery efforts.
Drug Efficacy, Safety, and Biologics Discovery, 2008
... The development of systems biology models in the pharmaceutical industry relies onknowledge o... more ... The development of systems biology models in the pharmaceutical industry relies onknowledge of drug targets in their biological context that has been codified and assembled from prior research studies reported in the literature. Page 14. ...
This article will highlight how traditional drug discovery is shifting towards integration of web... more This article will highlight how traditional drug discovery is shifting towards integration of web-based databases and tools. This integration is facilitating true online networked drug discovery collaborations -linking collaborators with both data and data analysis tools in a common platform. We will describe current notable efforts in this area and some of the key databases that are being used as resources for the collaborations. In particular, we discuss databases that are relevant to emerging discovery strategies, databases linking molecules, target and biological pathway data, databases that classify targets by drug action and databases that bridge to the growing pool of genomic data, such as the phenotype profiling of currently marketed drugs. These online efforts are innovative and accessible, and are able to expand the networks of research collaborators so they are able to contribute significantly to drug discovery projects, both locally and globally.
Page 1. 15 NOVEL APPLICATIONS OF KERNEL–PARTIAL LEAST SQUARES TO MODELING A COMPREHENSIVE ARRAY O... more Page 1. 15 NOVEL APPLICATIONS OF KERNEL–PARTIAL LEAST SQUARES TO MODELING A COMPREHENSIVE ARRAY OF PROPERTIES FOR DRUG DISCOVERY Sean Ekins, Mark J. Embrechts, Curt M. Breneman, Kam Jim, and Jean-Pierre Wery ...
Quantitative structure-activity relationship (QSAR) models have been developed for a dataset of 3... more Quantitative structure-activity relationship (QSAR) models have been developed for a dataset of 3133 compounds defined as either active or inactive against P. falciparum. Since the dataset was strongly biased towards inactive compounds, different sampling approaches were employed to balance the ratio of actives vs. inactives, and models were rigorously validated using both internal and external validation approaches. The balanced accuracy for assessing the antimalarial activities of 70 external compounds was between 87% and 100% depending on the approach used to balance the dataset. Virtual screening of the ChemBridge database using QSAR models identified 176 putative antimalarial compounds that were submitted for experimental validation, along with 42 putative inactives as negative controls. Twenty five (14.2%) computational hits were found to have antimalarial activities with minimal cytotoxicity to mammalian cells, while all 42 putative inactives were confirmed experimentally. Structural inspection of confirmed active hits revealed novel chemical scaffolds, which could be employed as starting points to discover novel antimalarial agents.
Integrated computational approaches for Mycobacterium tuberculosis (Mtb) are useful to identify n... more Integrated computational approaches for Mycobacterium tuberculosis (Mtb) are useful to identify new molecules that could lead to future tuberculosis (TB) drugs. Our approach uses information derived from the TBCyc pathway and genome database, the Collaborative Drug Discovery TB database combined with 3D pharmacophores and dual event Bayesian models of whole-cell activity and lack of cytotoxicity. We have prioritized a large number of molecules that may act as mimics of substrates and metabolites in the TB metabolome. We computationally searched over 200,000 commercial molecules using 66 pharmacophores based on substrates and metabolites from Mtb and further filtering with Bayesian models. We ultimately tested 110 compounds in vitro that resulted in two compounds of interest, BAS 04912643 and BAS 00623753 (MIC of 2.5 and 5 μg/mL, respectively). These molecules were used as a starting point for hit-to-lead optimization. The most promising class proved to be the quinoxaline di-N-oxides, evidenced by transcriptional profiling to induce mRNA level perturbations most closely resembling known protonophores. One of these, SRI58 exhibited an MIC = 1.25 μg/mL versus Mtb and a CC50 in Vero cells of >40 μg/mL, while featuring fair Caco-2 A-B permeability (2.3 x 10-6 cm/s), kinetic solubility (125 μM at pH 7.4 in PBS) and mouse metabolic stability (63.6% remaining after 1 h incubation with mouse liver microsomes). Despite demonstration of how a combined bioinformatics/cheminformatics approach afforded a small molecule with promising in vitro profiles, we found that SRI58 did not exhibit quantifiable blood levels in mice.
... A Case Study Sándor Szalma Collaboration in Cancer Research Community: Cancer Biomedical Info... more ... A Case Study Sándor Szalma Collaboration in Cancer Research Community: Cancer Biomedical Informatics Grid (caBIG) George A. Komatsoulis ... 24. Open Source Drug Discovery Model Anshu Bhardwaj, Vinod Scaria, Zakir Thomas, Santhosh Adayikkoth, Open Source Drug ...
Wikipedia has become the world’s most famous encyclopedia using as it’s platform the MediaWiki op... more Wikipedia has become the world’s most famous encyclopedia using as it’s platform the MediaWiki open source software. The software is supported not only by the MediaWiki foundation but by a community of developers who build widgets and add-ons to extend the capabilities. This presentation will review how MediaWiki has been used as a container for a number of resources of value to chemists, specifically SciMobileApps, SciDBs and ScientistsDB holding content regarding mobile scientific apps, scientific databases and scientists. We will also review how chemistry content within Wikipedia has been used to enhance the content underlying the RSC ChemSpider database and how the platform supports an educational environment for chemistry students.
There is an overwhelming number of new resources for chemistry that would likely benefit both lib... more There is an overwhelming number of new resources for chemistry that would likely benefit both librarians and students in terms of improving access to data and information. While commercial solutions provided by an institution may be the primary resources there is now an enormous range of online tools, databases, resources, apps for mobile devices and, increasingly, wikis. This presentation will provide an overview of how wiki-based resources for scientists are developing and will introduce a number of developing wikis. These include wikis that are being used to teach chemistry to students as well as to source information about scientists, scientific databases and mobile apps.
The human pregnane X receptor (PXR) is a ligand dependent transcription factor that can be activa... more The human pregnane X receptor (PXR) is a ligand dependent transcription factor that can be activated by structurally diverse agonists including steroid hormones, bile acids, herbal drugs, and prescription medications. PXR regulates the transcription of several genes involved in xenobiotic detoxification and apoptosis. Activation of PXR has the potential to initiate adverse effects by altering drug pharmacokinetics or perturbing physiological processes. Hence, more reliable prediction of PXR activators would be valuable for pharmaceutical drug discovery to avoid potential toxic effects. Ligand- and protein structure-based computational models for PXR activation have been developed in several studies. There has been limited success with structure-based modeling approaches to predict human PXR activators, which can be attributed to the large and promiscuous site of this protein. Slightly better success has been achieved with ligand-based modeling methods including quantitative structure-activity relationship (QSAR) analysis, pharmacophore modeling and machine learning that use appropriate descriptors to account for the diversity of the ligand classes that bind to PXR. These combined computational approaches using molecular shape information may assist scientists to more confidently identify PXR activators. This chapter reviews the various ligand and structure based methods undertaken to date and their results.
Nuclear receptors (NRs) are important biological macromolecular transcription factors that are im... more Nuclear receptors (NRs) are important biological macromolecular transcription factors that are implicated in multiple biological pathways and may interact with other xenobiotics that are endocrine disruptors present in the environment. Examples of important NRs include the androgen receptor (AR), estrogen receptors (ER), and the pregnane X receptor (PXR). In this study we have utilized the Ligand Activity by Surface Similarity Order (LASSO) method, a ligand-based virtual screening strategy to derive structural (surface/shape) molecular features used to generate predictive models of biomolecular activity for AR, ER, and PXR. For PXR, twentyfive models were built using between 8 to 128 agonists and tested using 3000, 8000, and 24,000 drug-like decoys including PXR inactive compounds ( = 228). Preliminary studies with AR and ER using LASSO suggested the utility of this approach with 2-fold enrichment factors at 20%. We found that models with 64-128 PXR actives provided enrichment factors of 10-fold (10% actives in the top 1% of compounds screened). The LASSO models for AR and ER have been deployed and are freely available online, and they represent a ligand-based prediction method for putative NR activity of compounds in this database.
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