Date of Degree

2-2022

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biochemistry

Advisor

Thomas Kurtzman

Committee Members

Gustavo Lopez

Wayne Harding

Prabodhika Mallikaratchy

Harel Weinstein

Subject Categories

Biophysics | Medicinal-Pharmaceutical Chemistry | Structural Biology

Keywords

water, opioid, SARS-CoV-2, docking, GIST, HSA

Abstract

Water-based Lead Generation. The opioid epidemic and the SARS-CoV-2 pandemic are current serious challenges whose devastating effects could be assuaged through the development of new drugs. Opioids that are functional painkillers, that are less likely to cause overdose, and small molecule drugs that could inhibit the life cycle of SARS-CoV-2 would be useful. The work herein investigated the use of water molecules for lead generation in drug development against opioid receptors and SARS-CoV-2 viral proteins. In opioid receptor binding sites, purported bridging waters were obtained from crystal waters or from molecular dynamics simulations, as Hydration Site Analysis was used to predict the locations and orientations of bridging water molecules. Hydration Site Analysis and Grid Inhomogeneous Solvation Theory were used to analyze solvated binding sites of SARS-CoV-2 proteins, to predict the locations and orientations of water molecules, and to produce thermodynamic analyses of water, which are useful to score solvation displacement in docking, inform lead modification, and create water-based pharmacophores, hybrid ligand- and water-based pharmacophores, and provide criteria to prioritize the selection of pharmacophore sites. This work demonstrated that the inclusion of bridging waters during ligand-receptor docking to opioid receptors improved docking enrichment by enhancing binding affinities via H-bond and electrostatic interactions and, in some cases, improved pose prediction. Inclusion of bridging water molecules helped to enrich known actives with or without a ligand core similar to the co-crystallized compound, and the selection of ligands (for whom interactions with bridging waters are important) can be automated. Inside the substrate-binding site of SARS-CoV-2 main protease, we find energetically unfavorable hydration sites whose displacement may lead to boosts in binding affinity, solvated regions of favorable or unfavorable energy density for use in a displaced solvent functional, and interesting hydration sites to create water-based pharmacophore elements for lone use, in combination with other ligand-based or structure-based pharmacophore elements, or for use in the prioritization of ligand- or structure-based pharmacophore elements.

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