A common feature-based 3D-pharmacophore model generation and virtual screening: identification of potential PfDHFR inhibitors

Adane, Legesse ; Bharatam, Prasad V. ; Sharma, Vikas (2010) A common feature-based 3D-pharmacophore model generation and virtual screening: identification of potential PfDHFR inhibitors Journal of Enzyme Inhibition and Medicinal Chemistry, 25 (5). pp. 635-645. ISSN 1475-6366

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Official URL: http://doi.org/10.3109/14756360903393817

Related URL: http://dx.doi.org/10.3109/14756360903393817

Abstract

A four-feature 3D-pharmacophore model was built from a set of 24 compounds whose activities were reported against the V1/S strain of the Plasmodium falciparum dihydrofolate reductase (PfDHFR) enzyme. This is an enzyme harboring Asn51Ile + Cys59Arg + Ser108Asn + Ile164Leu mutations. The HipHop module of the Catalyst program was used to generate the model. Selection of the best model among the 10 hypotheses generated by HipHop was carried out based on rank and best-fit values or alignments of the training set compounds onto a particular hypothesis. The best model (hypo1) consisted of two H-bond donors, one hydrophobic aromatic, and one hydrophobic aliphatic features. Hypo1 was used as a query to virtually screen Maybridge2004 and NCI2000 databases. The hits obtained from the search were subsequently subjected to FlexX and Glide docking studies. Based on the binding scores and interactions in the active site of quadruple-mutant PfDHFR, a set of nine hits were identified as potential inhibitors.

Item Type:Article
Source:Copyright of this article belongs to Informa UK Limited.
Keywords:Pharmacophore Model; Catalyst/Hip; Hopvirtual Screening Molecular Docking; P. Falciparum DHFR.
ID Code:116540
Deposited On:12 Apr 2021 10:08
Last Modified:12 Apr 2021 10:08

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