Analysis of raltegravir analogs to enhance inhibitory efficiency against HIV integrase

Abstract

This article addresses the improvement of the efficacy of anti-integrase enzyme drugs for the AIDS virus, especially using the drug Raltegravir and its 21 analogs. In this research, Hartree-Fock and Density Functional Theory methods have been employed for the design and optimization of new drug candidates. These methods are used to enhance the accuracy and reactivity of the drugs. Additionally, docking is used to investigate the interactions between the drug and the target and evaluate binding energies. Molecular dynamics simulation is utilized to validate binding results. Computational results indicate that the designed analogs exhibit higher reactivity. In molecular docking calculations, RAL5 and RAL21 show the best binding energies of -10.10 and - 10.92 kcal/mol, respectively, indicating their superior efficiency. The analysis of inhibitor potentials against the HIV-1 integrase enzyme through molecular dynamics simulation reveals that RAL5 has strong inhibitory potential for treating viral diseases. These findings contribute to the promotion of therapeutic intervention methods in this field.

Keywords: Drug design; HIV-1 integrase; Raltegravir; Viral disease treatment.

Fig. 1

Ramachandran diagrams of the 7RQ0 protein structure describing the favored and disallowed cases.

Fig. 2

Optimized 2D structure of Raltegravir (RAL) drug and new designed analogs.

Fig. 3

(A) 3D optimized structure and frontier orbital diagrams and (B) molecular electrostatic potential of RAL, RAL5 and RAL21 analogs.

Fig. 4

Hydrogen bonding and hydrophobic interactions of (A) RAL, (B) RAL5 and (C) RAL21 with the amino acids of HIV-IN binding site.

Fig. 5

(A) RMSD and (B) RMSF of Cα atoms of HIV-IN residues in HIV-IN/RAL (red), HIV-IN/RAL5 (blue), and HIV-IN/RAL21 (green) complexes.

Fig. 6

(A) Number of hydrogen bonds, (B) radius of gyration of Cα atoms, (C) PCA analysis, (D) number of contacts, (E) minimum distance and (F) solvent accessible surface diagram in HIV-IN/RAL (red), HIV-IN/RAL5 (blue) and HIV-IN/RAL21 (green), complexes.

Fig. 7

A graphical representation of the Gibbs free energy (FEL) landscape of the complexes: HIV-IN/RAL(A), HIV-IN/RAL5(B), and HIV-IN/RAL21(C), obtained from a molecular dynamics simulation study.