Specific Stereoisomeric Conformations Determine the Drug Potency of Cladosporin Scaffold against Malarial Parasite

Journal of Medicinal Chemistry
Pronay DasD Srinivasa Reddy

Abstract

The dependence of drug potency on diastereomeric configurations is a key facet. Using a novel general divergent synthetic route for a three-chiral center antimalarial natural product cladosporin, we built its complete library of stereoisomers (cladologs) and assessed their inhibitory potential using parasite-, enzyme-, and structure-based assays. We show that potency is manifest via tetrahyropyran ring conformations that are housed in the ribose binding pocket of parasite lysyl tRNA synthetase (KRS). Strikingly, drug potency between top and worst enantiomers varied 500-fold, and structures of KRS-cladolog complexes reveal that alterations at C3 and C10 are detrimental to drug potency whereas changes at C3 are sensed by rotameric flipping of glutamate 332. Given that scores of antimalarial and anti-infective drugs contain chiral centers, this work provides a new foundation for focusing on inhibitor stereochemistry as a facet of antimicrobial drug development.

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Citations

Nov 22, 2018·Chembiochem : a European Journal of Chemical Biology·Marion RuschLaure C Bouchez
Nov 9, 2019·Acta Crystallographica. Section F, Structural Biology Communications·Siddhartha MishraAmit Sharma
Feb 8, 2019·Malaria Journal·Dorothy Wavinya Nyamai, Özlem Tastan Bishop
Apr 5, 2020·International Journal of Molecular Sciences·Elizabeth Ruiz-MárvezConcepción J Puerta
Oct 16, 2019·Parasites & Vectors·Jyoti Chhibber-GoelAmit Sharma
Apr 13, 2021·ACS Infectious Diseases·Palak BabbarD Srinivasa Reddy
Mar 30, 2021·International Journal for Parasitology·Rini ChaturvediAmit Sharma
May 11, 2021·Chembiochem : a European Journal of Chemical Biology·Palak BabbarAmit Sharma
Jun 30, 2021·Protein Science : a Publication of the Protein Society·Jyoti Chhibber-GoelAmit Sharma

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Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.

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