Computational Design of Potent gp120 Receptor Antagonists via Docking and Molecular Dynamics Simulations and the gp120-CD4 Interaction

Abstract The gp120 receptor, a surface receptor of the HIV virus, is one of the key targets for designing drugs that inhibit the viral entry into the host cells. This study aims to design powerful drug-amino acid hybrids by utilizing existing gp120 inhibitors available on the market and the natural ligand of this molecule on host lymphocytes, CD4. Using docking and molecular dynamics simulations, the best candidates for future studies are proposed. In this study, drug-amino acid hybrids were designed by identifying the amino acids involved in the viral binding to its natural receptor in the host body. The chemically feasible connection sites to the inhibitory molecule of the receptor were identified and used for conjugation with amino acids. Virtual screening and molecular docking were used to identify in silico the strongest drug-amino acid hybrids. The pharmacokinetic properties and drug-likeness parameters of the selected hybrids were also assessed. Finally, molecular dynamics simulations were performed to evaluate the stability of the hybrid gp120 complex. Virtual screening, molecular docking, molecular dynamics simulations, and in silico evaluations of pharmacokinetic features led to four drug-amino acid hybrids derived from Temsavir. Two of them showed suitable pharmacodynamic properties and stability in binding to the receptor compared with Temsavir. The results of this study may facilitate future research for the development and rational design of new gp120 receptor inhibitors.