Identification of novel S-adenosyl-L-homocysteine hydrolase inhibitors through homology-model-based virtual screening, synthesis, and biological evaluation.
The present study describes a successful application of computational approaches to identify novel Leishmania donovani (Ld) AdoHcyase inhibitors utilizing the differences for Ld AdoHcyase NAD(+) binding between human and Ld parasite. The development and validation of the three-dimensional (3D) structures of Ld AdoHcyase using the L. major AdoHcyase as template has been carried out. At the same time, cloning of the Ld AdoHcyase gene from clinical strains, its overexpression and purification have been performed. Further, the model was used in combined docking and molecular dynamics studies to validate the binding site of NAD in Ld. The hierarchical structure based virtual screening followed by the synthesis of five active hits and enzyme inhibition assay has resulted in the identification of novel Ld AdoHcyase inhibitors. The most potent inhibitor, compound 5, may serve as a "lead" for developing more potent Ld AdoHcy hydrolase inhibitors as potential antileishmanial agents.
Parasitology Division, C.S.I.R.-Central Drug Research Institute, Lucknow, India.
Prashant
P
Khare
Amit K
AK
Gupta
Praveen K
PK
Gajula
Krishna Y
KY
Sunkari
Anil K
AK
Jaiswal
Sanchita
S
Das
Preeti
P
Bajpai
Tushar K
TK
Chakraborty
Anuradha
A
Dube
Anil K
AK
Saxena
D043383:Adenosylhomocysteinase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D007893:Leishmania donovani / Q000201:enzymology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009243:NAD / Q000378:metabolism; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013816:Thermodynamics; D014584:User-Computer Interface
D004791:Enzyme Inhibitors; D009243:NAD; D043383:Adenosylhomocysteinase