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

Das, Pronay ; Babbar, Palak ; Malhotra, Nipun ; Sharma, Manmohan ; Jachak, Goraknath R. ; Gonnade, Rajesh G. ; Shanmugam, Dhanasekaran ; Harlos, Karl ; Yogavel, Manickam ; Sharma, Amit ; Reddy, D. Srinivasa (2018) Specific Stereoisomeric Conformations Determine the Drug Potency of Cladosporin Scaffold against Malarial Parasite Journal of Medicinal Chemistry, 61 (13). pp. 5664-5678. ISSN 0022-2623

Full text not available from this repository.

Official URL: http://doi.org/10.1021/acs.jmedchem.8b00565

Related URL: http://dx.doi.org/10.1021/acs.jmedchem.8b00565

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.

Item Type:Article
Source:Copyright of this article belongs to American Chemical Society
ID Code:121857
Deposited On:22 Jul 2021 15:00
Last Modified:22 Jul 2021 15:00

Repository Staff Only: item control page