Homology modeling of falcipain-2: validation, de novo ligand design and synthesis of novel inhibitors

Journal of Biomolecular Structure & Dynamics
Yogesh SabnisM A Avery

Abstract

Increasing resistance of malaria parasites, in particular Plasmodium falciparum, demands a serious search for novel targets. Cysteine protease in P. falciparum, encoded by a previously unidentified gene falcipain 2, provides one such target to design chemotherapeutic agents for treatment of malaria. In fact, a few cysteine protease inhibitors have been shown to inhibit growth of cultured malarial parasites. In absence of a crystal structure for this enzyme, homology modeling proved to be a reasonable alternative to study binding requirements of the enzyme. A homology model for falcipain 2 was developed and validated by docking of known vinyl sulfone inhibitors. Further, based on the observations of these studies, novel isoquinoline inhibitors were designed and synthesized, which exhibited in vitro enzyme inhibition at micromolar concentrations.

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Citations

Jul 11, 2002·Molecular and Biochemical Parasitology·Manjit HanspalAthar H Chishti
Jul 26, 2006·Proceedings of the National Academy of Sciences of the United States of America·Stephanie X WangJames H McKerrow
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Sep 17, 2004·Biochemical and Biophysical Research Communications·Liuh Ling Goh, Tiow Suan Sim
Feb 12, 2017·Experimental Parasitology·Chandrajit DohutiaKishore Sarma
Feb 20, 2008·Journal of Biomolecular Structure & Dynamics·K V RameshSudha Deshmukh
Aug 12, 2017·Current Medicinal Chemistry·Rafael Pinto VieiraRafaela Salgado Ferreira
Apr 19, 2008·Journal of Chemical Information and Modeling·Prasenjit MukherjeeMitchell A Avery
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Jan 24, 2006·Journal of Chemical Information and Modeling·Visvaldas KairysMichael K Gilson

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