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Specific stereoisomeric conformations determine the drug potency of cladosporin scaffold against malarial parasite

DOI: 10.1021/acs.jmedchem.8b00565 DOI Help

Authors: Pronay Das (CSIR-National Chemical Laboratory; Academy of Scientific and Innovative Research (AcSIR)) , Palak Babbar (International Centre for Genetic Engineering and Biotechnology (ICGEB)) , Nipun Malhotra (International Centre for Genetic Engineering and Biotechnology (ICGEB)) , Manmohan Sharma (International Centre for Genetic Engineering and Biotechnology (ICGEB)) , Gorakhnath R. Jachak (CSIR-National Chemical Laboratory; Academy of Scientific and Innovative Research (AcSIR)) , Rajesh G. Gonnade (Academy of Scientific and Innovative Research (AcSIR); CSIR-National Chemical Laboratory) , Dhanasekaran Shanmugam (Academy of Scientific and Innovative Research (AcSIR); CSIR-National Chemical Laboratory) , Karl Harlos (Wellcome Trust Centre for Human Genetics, University of Oxford) , Manickam Yogavel (International Centre for Genetic Engineering and Biotechnology (ICGEB)) , Amit Sharma (International Centre for Genetic Engineering and Biotechnology (ICGEB)) , D. Srinivasa Reddy (CSIR-National Chemical Laboratory; Academy of Scientific and Innovative Research (AcSIR))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: May 2018
Diamond Proposal Number(s): 14744

Abstract: The dependence of drug potency on diastereomeric configurations is a key facet. Using a novel general divergent synthetic route for a three-chiral centre anti-malarial 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 where changes at C3 are sensed by rotameric flipping of Glutamate332. Given that scores of anti-malarial and anti-infective drugs contain chiral centers, this work provides a new foundation for focusing on inhibitor stereochemistry as a facet of anti-microbial drug development.

Journal Keywords: Oxides; Parasites; Assays; Molecular structure; Pharmaceuticals

Diamond Keywords: Malaria

Subject Areas: Chemistry, Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography

Other Facilities: SOLEIL

Added On: 29/05/2018 09:10

Discipline Tags:

Infectious Diseases Disease in the Developing World Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech Parasitology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)