Synthesis and structural studies of pentacycloundecane-based HIV-1 PR inhibitors: A hybrid 2D NMR and docking/QM/MM/MD approach

Makatini, Maya M.; Petzold, Katja; Sriharsha, S. N.; Ndlovu, Nombuso I.; Soliman, Mahmoud E. S.; Honarparvar, Bahareh; Parboosing, Raveen; Naidoo, Anushka; Arvidsson, Per I.; Sayed, Yasien; Gasqui, Patrick; Maguire, Glenn E. M.; Kruger, Hendrik G.; Govender, Thavendran

doi:10.1016/j.ejmech.2011.05.071

Cited by 35 publications

(34 citation statements)

References 57 publications

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“…Ribbon representation of overlay of modelled I36T↑T protease (brown) and wild‐type HIV‐1 subtype C (blue) previously reported (). The amino acid mutations (green), the amino acid insertion (red) and the catalytic Asp (yellow) are highlighted as spheres.…”

mentioning

confidence: 61%

“…The Leap module of amber12 package was used to add missing protons to the protein. Particularly, the protonation state of the catalytic Asp25 residue has been examined in our previous work and other studies, according to our previous investigations, showed that there is no significant difference between the binding free energy results for the monoprotonated and unprotonated states; therefore, the Asp25 residues in this study were left in the unprotonated state . The Amber force field for bioorganic systems (ff03.r1) was used in describing the parameters of the protein, while the inhibitors were described by GAFF parameters as implemented on amber12 .…”

Section: Methodsmentioning

confidence: 99%

“…Even though this subtype comprises 70% of the global HIV infection to date, very little experimental and computational work on the C‐SA protease has been reported. Publications investigating the impact of active site mutations on binding energies in the C‐SA protease and the inhibition thereof by pentacycloundecane lactam peptides and peptoids make up a substantial proportion of literature on C‐SA protease.…”

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confidence: 99%

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Binding Free Energy Calculations of Nine FDA‐approved Protease Inhibitors Against HIV‐1 Subtype C I36T↑T Containing 100 Amino Acids Per Monomer

et al. 2016

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In this work, have investigated the binding affinities of nine FDA-approved protease inhibitor drugs against a new HIV-1 subtype C mutated protease, I36T↑T. Without an X-ray crystal structure, homology modelling was used to generate a three-dimensional model of the protease. This and the inhibitor models were employed to generate the inhibitor/I36T↑T complexes, with the relative positions of the inhibitors being superimposed and aligned using the X-ray crystal structures of the inhibitors/HIV-1 subtype B complexes as a reference. Molecular dynamics simulations were carried out on the complexes to calculate the average binding free energies for each inhibitor using the molecular mechanics generalized Born surface area (MM-GBSA) method. When compared to the binding free energies of the HIV-1 subtype B and subtype C proteases (calculated previously by our group using the same method), it was clear that the I36T↑T proteases mutations and insertion had a significant negative effect on the binding energies of the non-pepditic inhibitors nelfinavir, darunavir and tipranavir. On the other hand, ritonavir, amprenavir and indinavir show improved calculated binding energies in comparison with the corresponding data for wild-type C-SA protease. The computational model used in this study can be used to investigate new mutations of the HIV protease and help in establishing effective HIV drug regimes and may also aid in future protease drug design.

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confidence: 61%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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Binding Free Energy Calculations of Nine FDA‐approved Protease Inhibitors Against HIV‐1 Subtype C I36T↑T Containing 100 Amino Acids Per Monomer

et al. 2016

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“…Cutoffs for the nonbonding interactions were applied by a switching scheme, within a 14 to 16 Å radius range. As the system was prebalanced, 2000 ps of QM/MM molecular dynamics was performed for each of the two systems, with steps of 0.001 ps [44,53,54].…”

Section: Molecular Dynamicsmentioning

confidence: 99%

Virtual Screening and Molecular Dynamics Simulations from a Bank of Molecules of the Amazon Region Against Functional NS3-4A Protease-Helicase Enzyme of Hepatitis C Virus

Pinheiro

Duarte

Alves

et al. 2015

Appl Biochem Biotechnol

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Hepatitis C virus (HCV) infection is a disease that affects approximately 3% of the global population and requires new therapeutic agents without the inconvenience associated with current anti-HCV treatment. This paper reports on a study of a virtual screening and a molecular dynamics simulation of compounds derived from natural products from the Amazon region that are potentially effective against the NS3-4A enzyme of HCV, which plays an important role in the replication process of this virus. According to the results of the molecular docking calculations and subsequent consensual analysis, the best scored compounds showed interactions between hydrogen and residues of the catalytic triad as well as interactions with residues that guide ligands to the active site of the enzyme. They also showed stability in the molecular dynamics simulation, as the structures preserved important interactions at the active site of the enzyme. The root mean square deviation (RMSD) values were stabilized at the end of the simulation time. Such compounds are considered promising as novel therapies against HCV.

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“…Until late 2012, the X‐ray crystal structure of the C‐SA PR was unavailable, limiting information on how drugs interact with this enzyme. A computational model for the C‐SA PR based on its protein sequence was developed [Mosebi et al., ] and used in previous studies [Makatini et al., 2011a, b, ; Honarparvar et al., ; Karpoormath et al., ]. Recently, the first X‐ray crystal structure of C‐SA HIV PR was reported [Naicker et al., ], allowing comparison of the unique structural and dynamic features of the C‐SA PR enzyme with subtype B.…”

Section: Introductionmentioning

confidence: 99%

A Hybrid Structure/Pharmacophore‐Based Virtual Screening Approach to Design Potential Leads: A Computer‐Aided Design of South African HIV‐1 Subtype C Protease Inhibitors

Soliman

2013

Drug Development Research

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Preclinical Research Virtual screening is the computational mirror image of high‐throughput screening and refers to the in silico evaluation of the biological activity of different molecular entities. Various virtual screening strategies and workflows have been adopted to enhance the process of identification of potential hits. Structure‐based scoring relies solely on the interactions between the ligand and the target protein. Conversely, pharmacophore‐based scoring relies on the shape complementation of each ligand candidate to a three‐dimensional reference ligand. Herewith, we report a systematic integrated hybrid approach, along with the use of well‐defined physicochemical and biological filters, to enhance high‐ranking hit structures complementing the binding site architecture while also mimicking the three‐dimensional features of known active ligands. With a lack of experimental data on the South African HIV protease enzyme (C‐SA HIV PR), very limited research has been conducted to design inhibitors against this enzyme variant. In this paper, a focused integrated structure‐ and pharmacophore‐based virtual screening protocol is introduced to identify potential leads to assist toward designing potent inhibitors against the C‐SA PR variant. This rapid and systematic approach can potentially be implemented for the design and discovery of inhibitors against a wide range of biological targets.

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Synthesis and structural studies of pentacycloundecane-based HIV-1 PR inhibitors: A hybrid 2D NMR and docking/QM/MM/MD approach

Cited by 35 publications

References 57 publications

Binding Free Energy Calculations of Nine FDA‐approved Protease Inhibitors Against HIV‐1 Subtype C I36T↑T Containing 100 Amino Acids Per Monomer

Binding Free Energy Calculations of Nine FDA‐approved Protease Inhibitors Against HIV‐1 Subtype C I36T↑T Containing 100 Amino Acids Per Monomer

Virtual Screening and Molecular Dynamics Simulations from a Bank of Molecules of the Amazon Region Against Functional NS3-4A Protease-Helicase Enzyme of Hepatitis C Virus

A Hybrid Structure/Pharmacophore‐Based Virtual Screening Approach to Design Potential Leads: A Computer‐Aided Design of South African HIV‐1 Subtype C Protease Inhibitors

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