Atom-based 3D-QSAR, molecular docking, DFT, and simulation studies of acylhydrazone, hydrazine, and diazene derivatives as IN-LEDGF/p75 inhibitors

Since HIV-1 integrase makes use of host genome machinery to accomplish the replication process, where LEDGF/p75 (a cellular cofactor) executes in the lentiviral integration process by interacting with integrase. Thus, the integrase-LEDGF/p75 interaction has become an interesting drug target in developing a potent agent. The purpose of the present study is to understand the inhibition mechanism with a structural basis of developed integrase inhibitors against viral infection. Herein, the computational approaches like atom-based 3D-QSAR, docking, MM/GBSA, DFT, and MDS were applied on a series of acylhydrazone, hydrazine, and diazene derivatives as integrase inhibitors. The developed 3D-QSAR model resulted in great predictive ability with training set (R-2 = 0.98, SD = 0.07) and for test set (Q(2) = 0.89, RMSE = 0.14, PearsonR = 0.90). The binding mode of interaction and involvement of energy on most and least active compounds into the LEDGF/p75 binding pocket of integrase were explored. We also observed that the predicted 3D-QSAR model has a good level of potential support by means of favorable and unfavorable regions of hydrogen bond donor, acceptor (electron-withdrawing), and hydrophobic groups for most active compound 7. This approach helps further to design anti-HIV inhibitors based on binding mode interaction and stability analysis.

Automated summary

The study utilized computational methods to investigate a series of integrase inhibitors, leading to the development of a 3D-QSAR model with high predictive ability. The research further explored the binding mode interaction and energy involvement of active compounds with integrase, providing insight for designing anti-HIV inhibitors based on stability analysis.