Discovery of HIV entry inhibitors via a hybrid CXCR4 and CCR5 receptor pharmacophore‐based virtual screening approach

Abstract

Chemokine receptors are key regulators of cell migration in terms of immunity and inflammation. Among these, CCR5 and CXCR4 play pivotal roles in cancer metastasis and HIV-1 transmission and infection. They act as essential co-receptors for HIV and furnish a route to the cell entry. In particular, inhibition of either CCR5 or CXCR4 leads very often the virus to shift to a more virulent dual-tropic strain. Therefore, dual receptor inhibition might improve the therapeutic strategies against HIV. In this study, we aimed to discover selective CCR5, CXCR4, and dual CCR5/CXCR4 antagonists using both receptor- and ligand-based computational methods. We employed this approach to fully incorporate the interaction attributes of the binding pocket together with molecular dynamics (MD) simulations and binding free energy calculations. The best hits were evaluated for their anti-HIV-1 activity against CXCR4- and CCR5-specific NL4.3 and BaL strains. Moreover, the Ca 2+ mobilization assay was used to evaluate their antagonistic activity. From the 27 tested compounds, three were identified as inhibitors: compounds 27 (CCR5), 6 (CXCR4) and 3 (dual) with IC 50 values ranging from 10.64 to 64.56 μM. The binding mode analysis suggests that the active compounds form a salt bridge with the glutamates and π-stacking interactions with the aromatic side chains binding site residues of the respective co-receptor. The presented hierarchical virtual screening approach provides essential aspects in identifying potential antagonists in terms of selectivity against a specific co-receptor. The compounds having multiple heterocyclic nitrogen atoms proved to be relatively more specific towards CXCR4 inhibition as compared to CCR5. The identified compounds serve as a starting point for further development of HIV entry inhibitors through synthesis and quantitative structure-activity relationship studies.

Discovery of anti-MERS-CoV small covalent inhibitors through pharmacophore modeling, covalent docking and molecular dynamics simulation

“…In this context, the main objectives of this study were to use a pharmacoinformatic approach and molecular dynamic simulation to explore novel covalent inhibitors of MERS-CoV 3CL pro . This approach has been successfully used to discover new drugs in a time- and cost-effective manners [ 55 , 57 , 58 ].…”

“…Representations in the above equations are: ΔG bind = binding energy; - T Δ S = entropic energy; ΔE MM = molecular mechanics potential energy [van der Waals (ΔE vdw ) energy + electrostatic (ΔE elec )]; ΔG sol = solvation free energy [polar solvation energy (ΔE polar ) + non-polar solvation energy (ΔE SASA ). MM/PBSA analysis has been widely used in binding free energy calculations for anti-viral inhibitors [ 32 , [49] , [50] , [51] , [52] , [53] , [54] , [55] ].…”

Pathogenesis and Treatment of Cytokine Storm Induced by Infectious Diseases

“…However, in practice, chemokine receptors have been difficult to antagonize, possibly reflecting the fact that such receptors engage in large numbers of diverse surface interactions with various chemokine ligands. Nevertheless, a few successful cases can be cited, such as that involving HIV co-receptors CCR5 and CXCR4, which were the first chemokine receptors targeted to block HIV entry into host cells [ 132 , 133 ]. Such early successes indicate that chemokine receptor antagonists show promise as targeted therapies for CRS [ 133 , 134 ].…”

“…Nevertheless, a few successful cases can be cited, such as that involving HIV co-receptors CCR5 and CXCR4, which were the first chemokine receptors targeted to block HIV entry into host cells [ 132 , 133 ]. Such early successes indicate that chemokine receptor antagonists show promise as targeted therapies for CRS [ 133 , 134 ]. Chemokine receptors may also serve as anti-CRS therapeutic targets based on their other functions, such as their regulation of host cell functional balance and functional stability.…”

Discovery of Novel CCR5 Ligands as Anticolorectal Cancer Agents by Sequential Virtual Screening

“…However, the identified compounds were less active compared to the control ligands MVC and AMD300. 17 Lin et al. screened the NCI database identifying potential CCR5 inhibitors with higher binding affinities than MVC as indicated by free energy calculations.…”