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Generating three-dimensional structure of polymorphic forms of CA-II using homology modeling and molecular dynamics

By Varsha Gupta and University of the Sciences in Philadelphia

	Three studies are presented here: (1) In the first part of the research, molecular dynamics (MD) simulation was used to study the structural differences arising from single nucleotide polymorphisms (SNPs) in carbonic anhydrase-II (CA-II). No difference in overall structure was observed because of the presence of single nucleotide polymorphism.(2) In the second part of the research, using a variety of computational tools over one million compounds from the ZINC database were screened and analyzed. 12 compounds predicted to act as inhibitors of carbonic anhydrase-II were identified. These compounds were obtained from several vendors, and all produced between 60-80% inhibition at an inhibitor concentration of 1 microM in a widely-used in vitro assay. Eleven of these compounds are expected to have very good lipid solubility (on the basis of predicted IogP), and bear no significant structural resemblance with commercially-available drugs. (3) In the last part of this dissertation substrates and enzyme-substrate complex structures are often the starting point of enzyme inhibitor design. Systematic characterization of the differences between substrates and inhibitors and their binding to enzymes is of help to our understanding of enzyme catalysis and to substrate-based inhibitor design. We have analyzed 329 high-resolution structures, representing 32 non-redundant enzymes in their free (apo), substrate bound, and inhibitor bound forms. Despite of the overall similarity between substrates and inhibitors, and their binding to enzymes, subtle differences were observed that could profoundly impact inhibitor design. This study is unrelated to (1) and (2) described above, and was carried out under the direction of Dr. ZhiJun Li of Department of Bioinformatics and Computer Science.
Publisher	ProQuest
ISBN	9781109012767
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