Identification of Novel Inhibitors of Leishmania donovani γ-Glutamylcysteine Synthetase Using Structure-Based Virtual Screening, Docking, Molecular Dynamics Simulation, and in Vitro Studies.
Trypansomatids maintain their redox balance by the trypanothione-based redox system, enzymes of which exhibit differences from mammalian homologues. γ-Glutamylcysteine synthetase (Gcs) is an essential enzyme in this pathway that performs the first and rate-limiting step. l-Buthionine-(S,R)-sulfoximine (BSO), a specific inhibitor of Gcs, induces toxicity in hosts infected with Trypanosoma brucei, underlining the need for novel Gcs inhibitors. The present study reports identification of Leishmania donovani Gcs (LdGcs) inhibitors using computational approaches and their experimental validation. Analysis of inhibitor-LdGcs complexes shows modifications that could result in increased efficacy of these compounds.
Molecular and Structural Biology Division, CSIR-Central Drug Research Institute , Lucknow-226031, India.
Pragati
P
Agnihotri
Molecular and Structural Biology Division, CSIR-Central Drug Research Institute , Lucknow-226031, India.
Arjun K
AK
Mishra
Molecular and Structural Biology Division, CSIR-Central Drug Research Institute , Lucknow-226031, India.
Shikha
S
Mishra
Division of Endocrinology, CSIR-Central Drug Research Institute , Lucknow-226031, India.
Vijay Kumar
VK
Sirohi
Molecular and Structural Biology Division, CSIR-Central Drug Research Institute , Lucknow-226031, India.
Amogh A
AA
Sahasrabuddhe
Molecular and Structural Biology Division, CSIR-Central Drug Research Institute , Lucknow-226031, India.
J Venkatesh
0000-0001-9181-1535
JV
Pratap
D000595:Amino Acid Sequence; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004151:Dipeptides / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects / Q000201:enzymology*; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D014584:User-Computer Interface
D000981:Antiprotozoal Agents; D004151:Dipeptides; D004791:Enzyme Inhibitors; C017341:gamma-glutamylcysteine