Robust Three-dimensional Tools to Design Inhibitors Against Drug Targets Which Lack Explicit Specificity
Conference Recording Apr 24, 2013
About the SpeakerDr. Moses Mohandas Prabu,PhD., is an Assistant Professor of Molecular, Leader of the Crystallography Laboratory, Division of Basic Sciences, The Commonwealth Medical College, USA. He received his B.Sc. & M.Sc. degrees in Physics with specialty in Optics. Dr. Prabu’s current research focus is in determining the rationale for molecular recognition of enzymes that proteolyze multiple amino acid sequences that share poor similarity. Specifically, his laboratory investigates the aspartyl proteases Plasmodium falciparum plasmepsins and human cathepsin D.
One of the measures to assess the success of a structure-based drug design operation is the ability to design chemical agents that specific block target’s activity. Inhibition of protein-protein/protein-ligand interactions for drug therapy can be achieved by designing inhibitors that mimic several molecular features of the natural interaction. However, drug targets that engage in promiscuous interactions with other proteins/ligands often exhibit high variability in the primary structural composition at the binding interface. HIV-1 protease is a highly suitable example of such a promiscuous target which specifically proteolyzes at cleavage sequences that share poor similarity. A combined investigation involving X-ray crystallography, biocalorimetry and molecular modeling confirmed that a consensus structural motif assumed by variable substrate sequences (aka substrate-envelope) is responsible for molecular recognition. In addition, the substrate-envelope also elucidates the structural correlation between drug resistance and substrate co-evolution, a crucial mechanism that allows viral efficacy amidst drug therapy. We therefore hypothesize that incorporation of factors intrinsic to substrate recognition in drug development will facilitate the design of novel potent drugs which will also help circumvent drug resistance. Our ongoing effort on other such enzymes with promiscuous recognition sites, such as human cathepsin D and malarial plasmepsins, will also be discussed.
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