Computer-aided drug design of falcipain inhibitors: virtual screening, structure-activity relationships, hydration site thermodynamics, and reactivity analysis

Journal of Chemical Information and Modeling
Falgun ShahMitchell A Avery

Abstract

Falcipains (FPs) are hemoglobinases of Plasmodium falciparum that are validated targets for the development of antimalarial chemotherapy. A combined ligand- and structure-based virtual screening of commercial databases was performed to identify structural analogs of virtual screening hits previously discovered in our laboratory. A total of 28 low micromolar inhibitors of FP-2 and FP-3 were identified and the structure-activity relationship (SAR) in each series was elaborated. The SAR of the compounds was unusually steep in some cases and could not be explained by a traditional analysis of the ligand-protein interactions (van der Waals, electrostatics, and hydrogen bonds). To gain further insights, a statistical thermodynamic analysis of explicit solvent in the ligand binding domains of FP-2 and FP-3 was carried out to understand the roles played by water molecules in binding of these inhibitors. Indeed, the energetics associated with the displacement of water molecules upon ligand binding explained some of the complex trends in the SAR. Furthermore, low potency of a subset of FP-2 inhibitors that could not be understood by the water energetics was explained in the context of poor chemical reactivity of the reactive centers of t...Continue Reading

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Citations

Apr 13, 2013·Journal of Computer-aided Molecular Design·G Madhavi SastryWoody Sherman
Oct 26, 2013·Journal of Computer-aided Molecular Design·Grace MugumbateRita C Guedes
Jun 20, 2014·Journal of Biomolecular Structure & Dynamics·I O Omotuyi, T Hamada
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May 5, 2016·Journal of Chemical Information and Modeling·Daniel RobinsonWoody Sherman
Jan 22, 2013·ACS Medicinal Chemistry Letters·Vassilios MyrianthopoulosAlexios-Leandros Skaltsounis

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