Molecular docking study of lamellarin analogues and identification of potential inhibitors of HIV-1 integrase strand transfer complex by virtual screening.

Molecular docking has been applied to elucidate the binding of lamellarin analogues with HIV-1 integrase strand transfer complex (PDB ID: 5U1C). The results suggest hydrogen bond interaction with residue Glu92 is key, and stabilisation by π-π stacking interactions with DNA base is chiefly influential to strand transfer activity. Other residues involved in hydrogen bonding are Cys65, His67, Asp64, Asp116 and chelation with Mg ion was seen for certain analogues. Furthermore, hydrophobic interactions can be accounted for several amino acids including Asp64, Cys65, Asp116, His67, Glu92, Tyr143, Phe121, Gly118, Pro142 and Val72, as well as the DNA base. The molecular docking results are in line with the reported literatures of other inhibitors and strand transfer activity observed previously by Faulkner. We further employed molecular docking simulation to virtually screen and identified 4 novel potential inhibitors of HIV-1 integrase strand transfer complex from a Chembridge diversity collection of 25,132 small molecule compounds; Chembridge ID compound codes: , , and . The candidates clearly formed hydrogen bonding interactions with important residues: His67 and Glu92. In addition, hydrophobic interactions were seen with residues similar to interactions with lamellarin analogues. The calculated drug-like scores are suggestive of these compounds to have clinical potential and ADMET predictions implied of their acceptable pharmacokinetic and toxicity profiles.