Improved prediction of HIV-1 protease-inhibitor binding energies by molecular dynamics simulations

Jenwitheesuk, Ekachai; Samudrala, Ram

doi:10.1186/1472-6807-3-2

Cited by 64 publications

(27 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…10 predicted to have the highest affinity using the molecular dynamics simulation and docking techniques. 6 The AG7088 inhibitor only partially fits into the binding pocket that the substrate would occupy, whereas the inhibitor with the highest binding affinity, L-700,417, mimics the substrate binding mode very well. …”

mentioning

confidence: 99%

“…6 The affinities have then been used to predict resistance/susceptibility for 1800 HIV-1 protease mutants/inhibitor combinations with greater than 90% accuracy. In a similar fashion, we have calculated the binding affinities of a variety of known HIV-1 protease inhibitors to the TGEV main proteinase.…”

mentioning

confidence: 99%

“…More details of our MD and docking protocols are available elsewhere. 6 Figure 1 lists our predicted binding affinities of 28 known inhibitors of HIV-1 protease as well as the compound proposed by Anand et al, to the TGEV proteinase structure. Of the 29 compounds evaluated, the inhibitor AG7088 is ranked 24th with low predicted binding affinity.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Identifying inhibitors of the SARS coronavirus proteinase

Jenwitheesuk

Samudrala

2003

Bioorganic & Medicinal Chemistry Letters

Self Cite

View full text Add to dashboard Cite

Abstract-The Severe Acute Respiratory Syndrome (SARS) is a serious respiratory illness that has recently been reported in parts of Asia and Canada. In this study, we use molecular dynamics (MD) simulations and docking techniques to screen 29 approved and experimental drugs against the theoretical model of the SARS CoV proteinase as well as the experimental structure of the transmissible gastroenteritis virus (TGEV) proteinase. Our predictions indicate that existing HIV-1 protease inhibitors, l-700,417 for instance, have high binding affinities and may provide good starting points for designing SARS CoV proteinase inhibitors. # 2003 Elsevier Ltd. All rights reserved.A novel coronavirus (CoV) has been isolated and identified as the cause of the severe acute respiratory syndrome (SARS), 1 for which there is currently no effective treatment. The SARS CoV genome sequence has been recently published. 2 The structure of the main proteinase, essential for SARS CoV replication, can be deduced from its similarity (43% sequence identity) to the X-ray crystallography structure of the proteinase from the porcine transmissible gastroenteritis virus (TGEV), also a coronavirus. 3 Anand et al., who solved the structure of the TGEV proteinase (PDB code: 1lvo), 4 have produced a model for the SARS CoV proteinase (PDB code: 1p9t and 1pa5) using the former as a template. In addition, they propose a drug discovered to treat the common cold, AG7088, as a good starting point for SARS CoV inhibition. AG7088 by itself has failed to inhibit the SARS CoV in vitro. 5 Here, using simulations, we show that HIV-1 protease inhibitors may provide better starting points than AG7088 for inhibition of the SARS CoV proteinase.Our computational simulation approaches use molecular dynamics (MD) and docking techniques, and have been applied to calculate the binding affinities of HIV-1 protease mutants and their inhibitors. 6 The affinities have then been used to predict resistance/susceptibility for 1800 HIV-1 protease mutants/inhibitor combinations with greater than 90% accuracy. In a similar fashion, we have calculated the binding affinities of a variety of known HIV-1 protease inhibitors to the TGEV main proteinase. Docking calculations were carried out using AutoDock version 3.0.5, with the Larmarckian genetic algorithm (LGA). 7 Since the structures of the TGEV and SARS CoV proteinases-inhibitor complexes have not been obtained, we therefore first performed preliminary docking experiments to identify the potential binding sites of the inhibitors by generating a grid box that is big enough to cover the entire surface of the protein. Docking runs were set to 100 to allow AutoDock to exhaustively find the potential binding sites of each inhibitor. The first ranked docking solution showed that all inhibitors bound to the substrate binding site of the TGEV and SARS proteinases.The protein-inhibitor complexes derived from the preliminary docking step were then immersed in TIP3-water shell and all atoms were allowed to relax using MD simulation. MD simula...

show abstract

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Identifying inhibitors of the SARS coronavirus proteinase

Jenwitheesuk

Samudrala

2003

Bioorganic & Medicinal Chemistry Letters

Self Cite

View full text Add to dashboard Cite

show abstract

“…Jenwitheesuk et al [20] reported that mutations in HR2 improve structural stability of the HR1/HR2 hairpin complex and may lead to enhancement of ENF resistance when present with resistant HR1 mutations.…”

Section: Emergence Of Enf-resistant Hiv-1 Mutantsmentioning

confidence: 98%

“…The authors reported that Asp f1 and its deletion mutant Asp f1 D (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) have been produced as recombinant proteins, and that the deleted aa sequence corresponds to an exposed NH 2 -terminal b-hairpin in Asp f1 protein. The NH 2 -terminal b-hairpin is highly flexible and has an exposed region, folded independently from the protein core.…”

Section: Ribotoxin Toxicity To Cells Ribonuclease Activity and Allermentioning

confidence: 99%

HIV-1 gp41 heptad repeat 2 (HR2) possesses an amino acid domain that resembles the allergen domain in Aspergillus fumigatus Asp f1 protein: review, hypothesis and implications

Becker

2007

Virus Genes

View full text Add to dashboard Cite

Enfuvirtide (ENF, T-20, Fuzeon) is the first synthetic peptide to be modeled according to the amino acid sequence of HIV-1 heptad repeat 2, which was used to treat cohorts of HIV-1-infected individuals who had failed to respond to treatment with the anti-HIV-1 cocktail HAART. It was reported that when injected subcutaneously, Enfuvirtide reduced viral RNA in patients' blood by 1.96 log(10), leading to a subsequent increase in the number of CD4(+) T cells in the blood. The drug treatment caused adverse effects at the injection site in a small number of treated individuals, and a gradual increase in IgE in the blood during prolonged treatment. Enfuvirtide was approved for treatment of HIV-1 patients who developed resistance to HAART. The present review attempts to explain the adverse effects of Enfuvirtide at the skin site of injection, and the gradual increase in IgE in patients' blood during treatment. These phenomena were reported to resemble the effect of allergens that cause asthma in humans. It is hypothesized that since the amino acid domain of the Asp f1 allergen from Aspergillus fumigatus was identified in the N-terminus of an 18 kDa protein, it may be useful to compare Asp f1 peptide aa 7-22 from the beta-hairpin sequence to the beta-hairpin sequence of the heptad repeat 2 of HIV-1 gp41. The comparison revealed that the amino acid sequence resembles part of the Asp f1 aa 7-22 allergenic domain. The heptad repeat 1 of gp41 also resembles the fungal allergen. It is suggested that the Enfuvirtide peptide be tested experimentally to determine if ENF peptide is capable of binding to IgE antibodies from Enfuvirtide-treated, HIV-1-infected patients, and whether the HR2-derived peptide is capable of inducing basophils that were isolated from healthy individuals and from ENF-treated and untreated HIV-1 patients to release histamine and IL-4.

show abstract