J Chem Inf Model - Identification of novel S-adenosyl-L-homocysteine hydrolase inhibitors through homology-model-based virtual screening, synthesis, and biological evaluation.

Tópicos

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Resumo

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.

Resumo Limpo

present studi describ success applic comput approach identifi novel leishmania donovani ld adohcyas inhibitor util differ ld adohcyas nad bind human ld parasit develop valid threedimension d structur ld adohcyas use l major adohcyas templat carri time clone ld adohcyas gene clinic strain overexpress purif perform model use combin dock molecular dynam studi valid bind site nad ld hierarch structur base virtual screen follow synthesi five activ hit enzym inhibit assay result identif novel ld adohcyas inhibitor potent inhibitor compound may serv lead develop potent ld adohci hydrolas inhibitor potenti antileishmani agent

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