Integrated virtual screening and molecular dynamics reveal novel Maraviroc analogues as optimized CCR5 entry inhibitors for HIV-1

The advancement of CCR5 antagonists is a vital approach in HIV-1 treatment to mitigate drug resistance and the toxicities of long-term antiretroviral therapy. This work utilized a combined ligand and receptor-based virtual screening workflow to discover novel Maraviroc derivatives. Initial similarity search of the ZINC in-stock database using ChemFP yielded 18 candidates, which were analyzed by molecular docking against the CCR5 receptor (PDB: 4MBS). Eight molecules displayed predicted docking scores more favorable than Maraviroc (-8.84 kcal/mol), led by ZINC001542979606 at -9.74 kcal/mol, although these differences fall within the inherent uncertainty of the scoring function. Multi-platform in silico ADMET analysis and molecular dynamics simulations revealed that the identified subset of analogues exhibits distinct trade-offs between computationally predicted safety profiles and thermodynamic binding stability. To assess temporal stability, molecular dynamics simulations were executed in a hydrated POPC lipid bilayer in triplicate (200 ns per replica), and MM-PBSA and LIE analyses were used to estimate binding free energies. These simulations demonstrated that while some analogues show improved predicted toxicological profiles, they often incur significant thermodynamic penalties or higher structural drift than Maraviroc. These results highlight ZINC001542979606 and ZINC000030691387 as theoretical leads that require in vitro validation to navigate the complex trade-offs involved in developing safer HIV-1 entry inhibitors.