Comparison of the Molecular Dynamics and Calculated Binding Free Energies for Nine FDA‐Approved HIV‐1 PR Drugs Against Subtype B and C‐SA HIV PR

Ahmed, Shaimaa M.; Kruger, Hendrik G.; Govender, Thirumala; Maguire, Glenn E. M.; Sayed, Yasien; Ibrahim, Mahmoud A. A.; Naicker, Previn; Soliman, Mahmoud E. S.

doi:10.1111/cbdd.12063

Cited by 32 publications

(45 citation statements)

References 69 publications

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“…A Q7K point mutation was introduced in the protease sequences by site-directed mutagenesis using the QuikChange Ò method (Stratagene, La Jolla, CA, USA) to reduce protease autocatalysis [57]. Expression and purification of the proteases were performed as previously described [6]. Briefly, transformed cells were induced to over-express the proteases as inclusion bodies using isopropyl-b-D-thiogalactopyranoside [58].…”

Section: Expression and Purificationmentioning

confidence: 99%

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Amide hydrogen exchange in HIV–1 subtype B and C proteases – insights into reduced drug susceptibility and dimer stability

et al. 2014

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Since its identification, HIV has continued to have a detrimental impact on the lives of millions of people throughout the world. The protease of HIV is a major target in antiviral treatment. The South African HIV–1 subtype C (C–SA) protease displays weaker binding affinity for some clinically approved protease inhibitors in comparison with the HIV–1 subtype B protease. The heavy HIV burden in sub‐Saharan Africa, where subtype C HIV–1 predominates, makes this disparity a topic of great interest. In light of this, the enzyme activity and affinity of protease inhibitors for the subtype B and C–SA proteases were determined. The relative vitality, indicating the selective advantage of polymorphisms, of the C–SA protease relative to the subtype B protease in the presence of ritonavir and darunavir was four‐ and tenfold greater, respectively. Dynamic differences that contribute to the reduced drug susceptibility of the C–SA protease were investigated by performing hydrogen–deuterium exchange/mass spectrometry (HDX/MS) on unbound subtype B and C–SA proteases. The reduced propensity to form the E35–R57 salt bridge, and alterations in the hydrophobic core of the C–SA protease, are proposed to affect the anchoring of the flexible flaps, resulting in an increased proportion of the fully open flap conformation. HDX/MS data suggested that the N–terminus of both proteases is less stable than the C–terminus of the proteases, thus explaining the increased efficacy of dimerization inhibitors targeted toward the C–terminus of HIV proteases. As far as we are aware, this is the first report on assessment of HIV protease dynamics using HDX/MS.

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Section: Expression and Purificationmentioning

confidence: 99%

“…Only recently has the crystal structure of the C-SA protease been elucidated [6], whereas the structure of the subtype B protease has been well studied. Structural comparison of the proteases does not definitively provide a clear basis for the differences in drug binding.…”

Section: Introductionmentioning

confidence: 99%

Amide hydrogen exchange in HIV–1 subtype B and C proteases – insights into reduced drug susceptibility and dimer stability

et al. 2014

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“…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%

“…This study employed a similar approach that was previously reported for the wild‐type C‐SA protease . The I36T↑T protease consists of 100 amino acids in each chain; the mutations and insertion are indicated in Figure .…”

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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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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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Comparison of the Molecular Dynamics and Calculated Binding Free Energies for Nine FDA‐Approved HIV‐1 PR Drugs Against Subtype B and C‐SA HIV PR

Cited by 32 publications

References 69 publications

Amide hydrogen exchange in HIV–1 subtype B and C proteases – insights into reduced drug susceptibility and dimer stability

Amide hydrogen exchange in HIV–1 subtype B and C proteases – insights into reduced drug susceptibility and dimer stability

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

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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