Dual targeting inhibitors for HIV-1 capsid and cyclophilin A: molecular docking, molecular dynamics, and quantum mechanics

The acquired immunodeficiency syndrome (AIDS), a progressive failure of the immune system that leads to death if left untreated, is caused by a member of a family of retroviruses known as human immunodeficiency virus type 1 (HIV-1). Virus capsid (CA) and human cyclophilin A (cyPA) are two important HIV-1 targets that are known for their primary role in the life cycle of the virus, making them attractive targets for HIV-1 drug discovery. This study used a dual targeting approach to inhibit these two targets utilising different in silico techniques. A library of 672 antiviral agents from the ChEMBL database was docked into the CA crystal structure. The obtained 10 best docking scores were used as queries in the PubChem database to search for similar structures. These analogs were then docked into CA and cyPA, resulting in 220 compounds with good docking scores on both targets, which were filtered by calculating MM-GBSA free binding energy and in silico pharmacokinetic properties. This led to the identification of 10 compounds with better docking scores and free binding energies with respect to CA and cyPA compared to the references. The best 3 compounds were further validated by molecular dynamics (MD) and density functional theory (DFT) calculations, which proved to have stable binding interactions and high reactivity. These compounds can be considered as potential double inhibitors of CA and cyPA, which are expected to achieve promising results in an experimental study.