Computer modeling and simulations of biological systems

Abu-Saleh, Abd Al-Aziz Ahmad (2021) Computer modeling and simulations of biological systems. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Computational chemistry plays a central role in chemistry and biophysics. By leveraging supercomputers, theoretical chemists can elucidate the atomic resolution of biological systems and solve chemical problems. This thesis consists of two parts: First, I worked on the challenging problem of understanding the enzymatic modification cation of aminoglycoside antibiotics by means of molecular modeling and simulation techniques. Aminoglycoside antibiotics were among the first tools of bacterial warfare found and used clinically and still have a central role in the treatment of acute bacterial infections. However, aminoglycoside modifying enzymes such as aminoglycoside phosphotransferases alter aminoglycoside antibiotics and, therefore, inactivate the drug. I elucidated the phosphorylation mechanism using quantum mechanical methods and molecular dynamics simulations. The results provide a new understanding of the aminoglycoside phosphotransferase catalytic function, which agrees with the available experimental data. Second, due to the emergence of the severe acute repository syndrome coronavirus SARS-CoV-2 in late 2019, I pivoted my efforts to try to gain insight into the rational design of potent inhibitors that target key proteins (e.g., the spike protein and the main protease) of SARS-CoV-2 coronavirus. The structure-based and ligand-based drug design were used to find effective therapeutics of SARS-CoV-2 disease. Interestingly, our results suggest several promising approved and bioactive inhibitors of SARS-CoV-2 main protease. Moreover, a comprehensive protocol including molecular docking, molecular dynamics simulations, standard binding energy calculations, and steered molecular dynamics simulations was performed to accelerate the discovery of compounds that would strongly bind to SARS-CoV-2 spike receptor binding domain (RBD), therefore, blocking viral attachment to the host cell. The discovered top hits identify critical interactions associated with the spike RBD protein, which in turn disrupt binding of the RBD protein to the host cell.

Item Type: Thesis (Doctoral (PhD))
Item ID: 15079
Additional Information: Includes bibliographical references.
Keywords: Aminoglycoside Antibiotics, Phosphorylation, SARS-CoV-2, COVID-19, Computational Chemistry
Department(s): Science, Faculty of > Chemistry
Date: August 2021
Date Type: Submission
Digital Object Identifier (DOI):
Library of Congress Subject Heading: Computational chemistry; Biological systems--Computer simulation; COVID-19 (Disease); Aminoglycosides.

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