Papers by Abdelazim M. A. Abdelagwwad
The dynamics of metal centers are challenging to describe due to the vast variety of ligands, met... more The dynamics of metal centers are challenging to describe due to the vast variety of ligands, metals, and coordination spheres, hampering the existence of transferable force field parameters for classical molecular dynamics simulations. Here we present easyPARM, a python-based tool able to calculate force field parameters for a wide range of metal complexes from routine frequency calculations with electronic structure methods. The approach is based on the unique labeling strategy, in which each ligand atom that coordinates the metal receives a unique atom type. This design prevents parameters shortage, labeling duplication, and the necessity to postprocess output files even for very complicated coordination spheres, whose parameterization process remain automatic. The program requires the Cartesian Hessian matrix, the geometry xyz
In this study we explore the molecular basis of combining photodynamic therapy (PDT), a light-tri... more In this study we explore the molecular basis of combining photodynamic therapy (PDT), a light-triggered targeted anticancer therapy, with the traditional chemotherapeutic properties of the well-known cytotoxic agent gemcitabine. A photosensitizer prerequisite is significant absorption of biocompatible light in the visible/near IR range, ideally between 600 and 1000 nm. We use highly accurate multiconfigurational CASSCF/MS-CASPT2/MM and TD-DFT methodologies to determine the absorption properties of a series of gemcitabine derivatives with the goal of red-shifting the UV absorption band toward the visible region and facilitating triplet state population. The choice of the substitutions and thus the rational design is based on important biochemical criteria and on derivatives whose synthesis is reported in the literature. The modifications tackled in this work consist of: i) substitution of the oxygen atom at O2 position with heavier atoms (O→S and O→Se) to red-shift the absorption band and increase the spin-orbit coupling, ii) addition of a lipophilic chain at the N7 position to enhance transport into cancer cells and slow down gemcitabine metabolism, and iii) attachment of aromatic systems at C5 position to further enhance redshift. Results indicate that the combination of these three chemical modifications markedly shifts the absorption spectrum towards the 500 nm region and beyond and drastically increases spin-orbit coupling values, two key PDT requirements. The obtained theoretical predictions encourage biological studies to further develop this anticancer approach.
DNA damage is ubiquitous in nature and is at the basis of emergent treatments such as photodynami... more DNA damage is ubiquitous in nature and is at the basis of emergent treatments such as photodynamic therapy, which is based on the activation of highly oxidative reactive oxygen species by photosensitizing O2. However, hypoxia observed in solid tumors imposes the necessity to devise oxygen-independent modes of action able to induce DNA damage under a low oxygen concentration. The complexity of these DNA damage mechanisms in realistic environments grows exponentially when taking into account light absorption and subsequent excited-state population, photochemical and (photo)-redox reactions, the multiple species involved in different electronic states, noncovalent interactions, multiple reaction steps, and the large number of DNA reactive sites. This work tackles all the intricate reactivity of a photosensitizer based on a nitroimidazole derivative reacting toward DNA in solution under UV light exposition. This is performed through a combination of ground- and excited-state quantum chemistry, classical molecular dynamics, and hybrid QM/MM simulations to rationalize in detail the formation of DNA interstrand cross-links (ICLs) exerted by the noncanonical noncovalent photosensitizer. Unprecedented spatial and temporal resolution of these phenomena is achieved, revealing that the ICL is sequence-specific and that the fastest reactions take place at AT, GC, and GT steps involving either the opposite nucleobases or adjacent Watson–Crick base pairs. The N7 and O6 positions of guanine, the N7 and N3 sites of adenine, the N4 position of cytosine, and the O2 atom of thymine are deemed as the most nucleophile sites and are positively identified to participate in the ICL productions. This work provides a multiscale computational protocol to study DNA reactivity with noncovalent photosensitizers, and contributes to the understanding of therapies based on photoinduced DNA damage at molecular and electronic levels. In addition, we believe the depth understanding of these processes should assist the design of new photosensitizers considering their molecular size, electronic properties, and the observed regioselectivity toward nucleic acids.
Cobaltabis(dicarbollide) anion ([o-COSAN] À) is a well-known metallacarborane with multiple appli... more Cobaltabis(dicarbollide) anion ([o-COSAN] À) is a well-known metallacarborane with multiple applications in a variety of fields. In aqueous solution, the cisoid rotamer is the most stable disposition in the ground state. The present work provides theoretical evidence on the possibility to photoinduce the rotation from the cisoid to the transoid rotamer, a conversion that can be reverted when the ground state is repopulated. The non-radiative decay mechanisms proposed in this work are coherent with the lack of fluorescence observed in 3D fluorescence mapping experiments performed on [o-COSAN] À and its derivatives. This phenomenon induced by light has the potential to destruct the vesicles and micelles cisoid [o-COSAN] À typically forms in aqueous solution, which could lead to promising applications, particularly in the field of nanomedicine.
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Papers by Abdelazim M. A. Abdelagwwad