Binding free energies; HIV PR inhibitors; HIV subtype B/C-SA PR; Inhibitor—enzyme interactions; Our Own N-layered Integrated molecular Orbital and molecular Mechanics (ONIOM); HIV Protease Inhibitors; HIV Protease; Catalytic Domain/drug effects; Entropy; HIV Infections/drug therapy; HIV Protease/metabolism; HIV Protease Inhibitors/pharmacology; HIV-1/drug effects; HIV-1/metabolism; Humans; Hydrogen Bonding/drug effects; Quantum Theory; Thermodynamics; United States; United States Food and Drug Administration; Binding free energy; Computational model; Enzyme interaction; Explicit water molecules; Food and drugs administrations; Structural insights; Sub-Sahara Africa; Catalytic Domain; HIV Infections; HIV-1; Hydrogen Bonding; Spectroscopy; Physical and Theoretical Chemistry; Computer Graphics and Computer-Aided Design; Materials Chemistry
Abstract :
[en] Human immune virus subtype C is the most widely spread HIV subtype in Sub-Sahara Africa and South Africa. A profound structural insight on finding potential lead compounds is therefore necessary for drug discovery. The focus of this study is to rationalize the nine Food and Drugs Administration (FDA) HIV antiviral drugs complexed to subtype B and C-SA PR using ONIOM approach. To achieve this, an integrated two-layered ONIOM model was used to optimize the geometrics of the FDA approved HIV-1 PR inhibitors for subtype B. In our hybrid ONIOM model, the HIV-1 PR inhibitors as well as the ASP 25/25' catalytic active residues were treated at high level quantum mechanics (QM) theory using B3LYP/6-31G(d), and the remaining HIV PR residues were considered using the AMBER force field. The experimental binding energies of the PR inhibitors were compared to the ONIOM calculated results. The theoretical binding free energies (?Gbind) for subtype B follow a similar trend to the experimental results, with one exemption. The computational model was less suitable for C-SA PR. Analysis of the results provided valuable information about the shortcomings of this approach. Future studies will focus on the improvement of the computational model by considering explicit water molecules in the active pocket. We believe that this approach has the potential to provide much improved binding energies for complex enzyme drug interactions.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Sanusi, Z K; Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa
Govender, T; Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa
Maguire, G E M; Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa, School of Chemistry and Physics, University of KwaZulu-Natal, 4001 Durban, South Africa
Maseko, Sibusiso Bonginkhost ; Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa
Lin, J; School of Life Sciences, University of KwaZulu-Natal, Durban 4001, South Africa
Kruger, H G; Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa. Electronic address: kruger@ukzn.ac.za
Honarparvar, B; Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa. Electronic address: Honarparvar@ukzn.ac.za
Language :
English
Title :
Investigation of the binding free energies of FDA approved drugs against subtype B and C-SA HIV PR: ONIOM approach.
We thank the College of Health Sciences (CHS), Aspen Pharma-care, MRC and the NRF for financial support. We are also gratefulto the CHPC (www.chpc.ac.za) and UKZN HPC cluster as our com-putational resources.
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