Profiling the interaction mechanism of indole-based derivatives targeting the HIV-1 gp120 receptor

A glycoprotein exposed on a viral surface, human immunodeficiency virus type 1 (HIV-1) gp120 is essential for virus entry into cells as it plays a vital role in seeking out specific cell surface receptors for entry. The CD4 binding site of gp120 is known to be highly conserved among the different circulating subtypes and therefore constitutes particularly interesting targets for drug design. The rational selection of the training and test sets is a crucial step in the process of establishing three-dimensional quantitative structure–activity relationship (3D-QSAR) models. In the present study, a novel rational division methodology based on a genetic algorithm (GA) was employed for building QSAR models. In order to verify the rationality of the GA splitting approach, the modeling set was subdivided into a training set (80% of the modeling set) and a test set (20% of the modeling set) using a self-organizing map (SOM) and random division for comparison. The models of SOM and random splitting exhibit almost the same proper statistical results (Table 5) indicating that models based on these three division methods generate significant statistical results for the test sets, proving the reasonability of the GA division method for building the models. In addition, molecular docking, molecular dynamics (MD) and Molecular Mechanics/Poisson–Boltzmann Surface Area (MM-PBSA) were performed for further extending the study and confirming the goodness of the CoMFA and CoMSIA models. The corresponding 3D contour maps along with the docking and MD simulation results have also identified the key structural requirements of HIV-1 inhibitors responsible for the activity: (1) bulky substituent at position-3 of the oxazole ring increases the biological activity; (2) electrostatic groups at positions-2,3 of the oxazole ring and positions-14,15 of the indole ring are helpful for the HIV-1 inhibition; (3) hydrophobic groups at position-12 of indole are favored. (4) Asp368, Asn425, Thr257, Ser375, Asp474, Gly473 form several H-bonds which are crucial for the ligand–target interactions. The decomposition of free energies by MM-PBSA indicates the polar salvation contribution terms are the major driving force for the interaction between the inhibitor and HIV-1 protein. The present work provides useful guidelines for future structural modifications of this class of compounds towards the development of superior HIV-1 inhibitors.