Identification of Novel 3-Hydroxy-pyran-4-One Derivatives as Potent HIV-1 Integrase Inhibitors Using in silico Structure-Based Combinatorial Library Design Approach

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.

Structure-activity relationships study of isothiocyanates for H2S releasing properties: 3-Pyridyl-isothiocyanate as a new promising cardioprotective agent

“…Notably, at the beginning of drug discovery trajectory it is particularly important to prioritize potential hit compounds that could be suitable starting points for searching novel drug candidates. Accordingly, it is a common procedure, during the drug discovery pipeline, consider some molecular descriptors for selecting potential drug candidates with satisfactory physicochemical properties and ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile [29] , [37] , [38] , [39] . Accordingly, we performed an in silico analysis to determine which derivatives could be submitted to further cellular and in vivo studies.…”

New cinnamid and rosmarinic acid derived compounds biosynthesized inEscherichia coliasLeishmania amazonensisarginase inhibitors

“…The energy grid was prepared using the default value of the protein atom scaling factor (1.0 Å) within a cubic box centered on the crystallized ligand nor-NOHA. As part of grid generation procedure, metal constraints for the receptor grids were also applied [27, 28] . After grid generation, the ligands were docked into the enzymes considering the metal constraints.…”

Cinnamides Target Leishmania amazonensis Arginase Selectively

“…The energy grid was prepared using the default value of the protein atom scaling factor (1.0 Å), within a cubic box centered on the crystallized ligand nor-NOHA for L-ARG, while for the modelled protein the cubic box was centered on metal ions. As part of the grid generation procedure, metal constraints for the receptor grids were also applied [43,44]. After the grid generation, the ligands were docked into the enzymes, considering the metal constraints.…”