Title:Unveiling Novel HIV-1 Protease Inhibitors through an Integrated Analysis of 3D-QSAR, Molecular Docking, and Binding Free Energy
Volume: 21
Author(s): Guozheng Zhou, Yujie Shi and Yan Li*
Affiliation:
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian, Liaoning, 116024, China
Keywords:
HIV-1 PIs, CoMFA, CoMSIA, 3D-QSAR, molecular docking, DRV derivatives.
Abstract: Introduction: HIV-1, the primary causative agent of AIDS, remains a formidable and
lethal virus globally, claiming the lives of millions over the past four decades since its discovery.
Recent research has underscored the potential of HIV-1 protease as a therapeutic target, offering a
promising strategy for inhibiting viral replication within the body.
Method: In light of this, we have curated an extensive database comprising 193 derivatives of Darunavir
(DRV), an HIV-1 protease inhibitor. Simultaneously, we have developed a comprehensive
set of 3D-QSAR models to elucidate the structure-activity relationships of these 193 derivative inhibitors.
Employing various computational simulation techniques, including Comparative Molecular
Field Analysis (CoMFA), Comparative Similarity Indices Analysis (CoMSIA), and molecular docking,
we have unveiled the fundamental three-dimensional structural features influencing their biological
activity.
Result: Results indicate that the optimal CoMSIA model (Q2 = 0.500, R2
ncv = 0.882, R2
pred = 0.797)
surpasses other models, demonstrating superior predictive capability. Furthermore, docking results
suggest that DRV derivatives maintain stable conformations within the binding cavity due to synergistic
interactions, such as hydrogen bonding and non-bonded interactions. Drawing insights from
the best computational models, we have designed five DRV derivatives with significant HIV-1 protease
inhibitory activity through local modification, with theoretical calculations indicating favorable
pharmacokinetic properties and synthetic feasibility for the newly proposed molecules.
Conclusion: It is hoped that the findings and conclusions obtained herein may furnish theoretical
underpinning and directional guidance for the design, optimization, and experimental synthesis of
DRV derivative compounds for pharmaceutical purposes.
