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.
Highlights
HIV-1 integrase (IN) represents an attractive target in anti-HIV drug design mainly due to its specificity
The main purpose of the present study is to identify novel chemical entities derived from hydroxyl-pyran-4-one-2-carboxamide derivatives (HPCARs) scaffold as new and useful hit compounds as HIV-1 INIs
An integrated computational protocol based on combinatorial library design protocol, physico-chemical properties prediction, molecular docking calculations, and molecular dynamics (MD) simulation was developed in a stepwise filtering approach (Figure 3)
Summary
HIV-1 integrase (IN) represents an attractive target in anti-HIV drug design mainly due to its specificity. HIV-1 IN does not have a functional equivalent in humans and plays a unique role in establishing irreversible and productive viral infections (Debyser et al, 2002; Delelis et al, 2008). This viral key enzyme catalyzes the insertion of proviral DNA, derived from reverse transcription of HIV-1 RNA, into the genome of the host-infected cells. A the covalent joining of the two DNA strands is observed (Chiu and Davies, 2004; Pommier et al, 2005) Both reactions are accomplished by the catalytic core domain of HIV-1 IN which contains two divalent metal ion cofactors (Mg2+). These metal ions are coordinated by three catalytic carboxylate residues: Asp, Asp116, and Glu152 (DDE triad) within the enzyme active site (Dyda et al, 1994; Neamati et al, 2002)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
