Elucidating the Inhibiting Mode of AHPBA Derivatives against HIV-1 Protease and Building Predictive 3D-QSAR Models

Abstract

The Lamarckian genetic algorithm of AutoDock 3.0 has been used to dock 27 3(S)-amino-2(S)-hydroxyl-4-phenylbutanoic acids (AHPBAs) into the active site of HIV-1 protease (HIVPR). The binding mode was demonstrated in the aspects of the inhibitor's conformation, subsite interaction, and hydrogen bonding. The data of geometrical parameters (τ 1 , τ 2 , and τ 3 listed in Table 2) and root mean square deviation values as compared with the known inhibitor, kni272, 28 show that both kinds of inhibitors interact with HIVPR in a very similar way. The r 2 value of 0.860 indicates that the calculated binding free energies correlate well with the inhibitory activities. The structural and energetic differences in inhibitory potencies of AHPBAs were reasonably explored. Using the binding conformations of AHPBAs, consistent and highly predictive 3D-QSAR models were developed by performing CoMFA, CoMSIA, and HQSAR analyses. The reasonable r corss 2 values were 0.613, 0.530, and 0.717 for CoMFA, CoMSIA, and HQSAR models, respectively. The predictive ability of these models was validated by kni272 and a set of nine compounds that were not included in the training set. Mapping these models back to the topology of the active site of HIVPR leads to a better understanding of vital AHPBA-HIVPR interactions. Structural-based investigations and the final 3D-QSAR results provide clear guidelines and accurate activity predictions for novel HIVPR inhibitors.

Classical QSAR Modeling of HIV‐1 Reverse Transcriptase Inhibitor 2‐Amino‐6‐arylsulfonylbenzonitriles and Congeners

“…QSAR analysis of anti-HIV drugs was performed on phosphoramidate derivatives [19] using Hansch analysis. Using the binding conformations of 3-amino-2-hydroxy-4-phenylbutanoicacids [20] into the active site of HIV-1 protease, highly predictive 3D-QSAR models were developed by CoMFA, CoMSIA, and HQSAR analyses.…”

Modification and biological evaluation of novel 4-hydroxy-pyrone derivatives as non-peptidic HIV-1 protease inhibitors

“…Since the phenyl group at the C-6 position of the pyrone ring was reported to improve the inhibitory activity, we assumed that the observed impressed activity could be due to the inserted heteroatoms. The compounds were docked into the binding site of HIV-1 PR structure using AutoDock3.0 program (Morris et al, 1998;Huang et al, 2002). Figure 2 from docking result showed that the phenyl group at C-6 position of the pyrone ring could fit the S 1 pocket very well as predicted.…”

“…Furthermore, the structures were docked to the binding sites of HIV-1 PR using AutoDock3.0 program (Morris et al, 1998;Huang et al, 2002), to investigate the interaction characteristics between respective compound and HIV-1 PR.…”

Correlation between the predicted and the observed biological activity of the symmetric and nonsymmetric cyclic urea derivatives used as HIV‐1 protease inhibitors. A 3D‐QSAR‐CoMFA method for new antiviral drug design

“…The resistance of the HIV-1 PR mutants obliged us to apply very fast and precise techniques, able to predict the biological activity for the new HIV-1 PR inhibitors. QSAR (quantitative structureactivity relation) techniques [12][13][14], especially 3D-QSAR-CoMFA (Comparative Molecular Field Analysis) or 3D-QSAR-CoMSIA (Comparative Molecular Similarity Analysis) [15][16][17][18][19][20] proved to be very useful when the HIV-1 PR inhibitors potency are to be predicted. In the last years, a good correlation between the predicted and the observed biological activity for the HIV-1 PR cyclic urea inhibitors was reported [16,20,21].…”