Molecular docking and dynamic simulation studies for antiretroviral activity of phytochemicals isolated from Croton dichogamus

The Human Immunodeficiency Virus (HIV) infection and the associated acquired immune deficiency syndrome (AIDS) remain global challenges even after decades of successful treatment, with Eastern and Southern Africa still bearing the highest burden of disease. To search for potential anti-HIV compounds from natural products, we subjected 28 phytochemicals previously isolated from Croton dichogamus to molecular docking and dynamic simulation studies against HIV-1 reverse transcriptase enzyme (PDB ID: 1REV). Molecular docking was performed using Autodock 4.2.6, while molecular dynamic simulations were performed for 100ns for compounds with top docking poses using the Desmond package, Schrodinger. Based on our findings, we report five potential inhibitors of HIV-1 RT, including aleuritolic acid, furocrotinsulolide A, crotoxide A, crotohaumanoxide, and Crothalimene A, with respective free binding energies of -173.52, -40.53, -38.07, -35.78, and -32.73 kcal/mol. These compounds have shown high free binding energy as compared to standard FDA-approved antiretroviral drugs. Our computational studies have also shown that these phytochemicals form hydrophobic interactions with ASN 265, GLU 378, GLY 352, HIS 96, ILE 382, SER 268, TRP 266, hydrogen bonding with ARG 355, ARG 356, ARG 358, GLN 269, ILE 94, LEU 92, LYS 350, LYS 353, LYS 374, TYR 232 amino acids in the active site of the enzyme. Thus, we report these top 5 phytochemicals as potentially potent, selective, orally bioavailable, and nontoxic leads based on the ADMET screening and effective binding analysis in the active site of the reverse transcriptase (PDB ID: 1REV) for further consideration.