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Identification of Novel 3-Hydroxy-Pyran-4-One Derivatives As Potent Hiv-1 Integrase Inhibitors Using in Silico Structure-Based Combinatorial Library Design Approach Publisher



Sirous H1 ; Chemi G2 ; Gemma S2 ; Butini S2 ; Debyser Z3 ; Christ F3 ; Saghaie L4 ; Brogi S5 ; Fassihi A4 ; Campiani G2 ; Brindisi M6
Authors
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Authors Affiliations
  1. 1. Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
  2. 2. Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022, University of Siena, Siena, Italy
  3. 3. Molecular Medicine, K.U. Leuven and IRC KULAK, Leuven, Belgium
  4. 4. Department of Medicinal Chemistry, Faculty of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran
  5. 5. Department of Pharmacy, University of Pisa, Pisa, Italy
  6. 6. Department of Pharmacy, Department of Excellence 2018-2022, University of Naples Federico II, Naples, Italy

Source: Frontiers in Chemistry Published:2019


Abstract

We describe herein the development and experimental validation of a computational protocol for optimizing a series of 3-hydroxy-pyran-4-one derivatives as HIV integrase inhibitors (HIV INIs). Starting from a previously developed micromolar inhibitors of HIV integrase (HIV IN), we performed an in-depth investigation based on an in silico structure-based combinatorial library designing approach. This method allowed us to combine a combinatorial library design and side chain hopping with Quantum Polarized Ligand Docking (QPLD) studies and Molecular Dynamics (MD) simulation. The combinatorial library design allowed the identification of the best decorations for our promising scaffold. The resulting compounds were assessed by the mentioned QPLD methodology using a homology model of full-length binary HIV IN/DNA for retrieving the best performing compounds acting as HIV INIs. Along with the prediction of physico-chemical properties, we were able to select a limited number of drug-like compounds potentially displaying potent HIV IN inhibition. From this final set, based on the synthetic accessibility, we further shortlisted three representative compounds for the synthesis. The compounds were experimentally assessed in vitro for evaluating overall HIV-1 IN inhibition, HIV-1 IN strand transfer activity inhibition, HIV-1 activity inhibition and cellular toxicity. Gratifyingly, all of them showed relevant inhibitory activity in the in vitro tests along with no toxicity. Among them HPCAR-28 represents the most promising compound as potential anti-HIV agent, showing inhibitory activity against HIV IN in the low nanomolar range, comparable to that found for Raltegravir, and relevant potency in inhibiting HIV-1 replication and HIV-1 IN strand transfer activity. In summary, our results outline HPCAR-28 as a useful optimized hit for the potential treatment of HIV-1 infection by targeting HIV IN. © Copyright © 2019 Sirous, Chemi, Gemma, Butini, Debyser, Christ, Saghaie, Brogi, Fassihi, Campiani and Brindisi.
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