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Identification of novel inhibitors of HIV-1 integrase using pharmacophore-based virtual screening combined with molecular docking strategies

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Abstract

Human immunodeficiency virus type-1 (HIV-1) integrase is one of three enzymes encoded by the HIV genome for effective viral replication, and therefore an attractive target for chemotherapeutic interventions in the development of AIDS treatment. In this study, chemical feature-based pharmacophore models of different classes of integrase strand transfer inhibitors have been developed. The best HypoRefine pharmacophore models, Hypo1, which have the best correlation coefficients (0.92) and the lowest RMSs (0.78), contain two hydrogen bond acceptor lipids, one hydrogen bond donor, and one hydrophobic aromatic with four excluded volumes. After filtering by Lipinski’s rule of five, the best pharmacophore model was utilized as a 3D search query to perform a virtual screening to retrieve potential inhibitors. The hit compounds were subsequently subjected to docking studies by GOLD program to refine the retrieved hits. Finally, 4 top ranked compounds based on GOLD score fitness function and rescoring by X-score were investigated for compliance with the standard ranges through in silico ADME studies.

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Authors and Affiliations

  1. Chemistry Department, Faculty of Sciences, K. N. Toosi University of Technology, Tehran, Iran

    Anahita Ardakani & Jahan B Ghasemi

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  1. Anahita Ardakani
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  2. Jahan B Ghasemi
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Correspondence to Jahan B Ghasemi.

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Ardakani, A., Ghasemi, J.B. Identification of novel inhibitors of HIV-1 integrase using pharmacophore-based virtual screening combined with molecular docking strategies. Med Chem Res 22, 5545–5556 (2013). https://doi.org/10.1007/s00044-013-0545-0

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