DOI
https://doi.org/10.25772/BB2T-8B08
Author ORCID Identifier
orcid.org/0000-0002-7532-6318Defense Date
2017
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmaceutical Sciences
First Advisor
Glen E. Kellogg
Abstract
Hydropathic molecular modeling is a computer-aided molecular design technique for obtaining, representing, and understanding the properties and interactions of biomacromolecular complexes in the biological environment. Hydropathic INTeraction (HINT) is a novel empirical force field to calculate the free energy of intermolecular interaction based on experimentally determined partition coefficients (log Po/w). It includes all the expected interactions between molecules such as hydrogen bonding, hydrophobic, electrostatic, acid-base, and Coulombic interactions, entropy, solvation and others. HINT tools were used to determine, evaluate, and analyze protein-ligand interactions in different research projects:
1) We used these tools to discover small molecule inhibitors of PsaA, a potential target for Streptococcus pneumoniae. We screened and scored potential molecules to obtain hits. After the growth conditions for both the wild type and PsaA mutant of S. pneumoniae were optimized, we then tested our hits. A few compounds passed through the three-stage assay protocol and confirmed the inhibition of PsaA with MICs between 125-250 μM.
2) The SAR of C-3 and C-5 pyrrole-based antitubulin agents at the colchicine-binding site with explicitly solvated models was performed. After docking with GOLD at the colchicine site, post-docking scoring and evaluation were performed with HINT. The total HINT score correlates with binding and activity; similarly, the significance of individual functional groups, protein residues and interactions amongst a collection of compounds can be quantitated. The possibility of water-mediated interactions in a way solvent accessible part of the pocket was considered by subjecting molecular models to MD simulations. Several water molecules were identified to be contributing to the binding and were confirmed by HINT scoring.
Finally, using hydropathic molecular modeling tools helped us to understand, evaluate, analyze, and improve protein-ligand interactions in different biological systems.
Rights
© Ahmad J. Obaidullah
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
12-5-2017
Included in
Bacterial Infections and Mycoses Commons, Chemicals and Drugs Commons, Health Information Technology Commons, Pharmaceutics and Drug Design Commons