Bridge water mediates nevirapine binding to wild type and Y181C HIV-1 reverse transcriptase—Evidence from molecular dynamics simulations and MM-PBSA calculations

Treesuwan, Witcha; Hannongbua, Supa

doi:10.1016/j.jmgm.2009.02.007

Cited by 24 publications

(25 citation statements)

References 50 publications

(57 reference statements)

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“…We retained the water molecules found in the active sites of each protein for all the simulations used here as they have been shown to be critical in protein-ligand simulations in the past [19,20]. Water molecules have been shown to be important for rationalizing dynamic phenomena from MD simulations [21] as well as docking and scoring results [22,23].…”

Section: Protein Preparationmentioning

confidence: 99%

Computational study of EGFR inhibition: molecular dynamics studies on the active and inactive protein conformations

2012

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The structural diversity observed across protein kinases, resulting in subtly different active site cavities, is highly desirable in the pursuit of selective inhibitors, yet it can also be a hindrance from a structure-based design perspective. An important challenge in structure-based design is to better understand the dynamic nature of protein kinases and the underlying reasons for specific conformational preferences in the presence of different inhibitors. To investigate this issue, we performed molecular dynamics simulation on both the active and inactive wild type epidermal growth factor receptor (EGFR) protein with both type-I and type-II inhibitors. Our goal is to better understand the origin of the two distinct EGFR protein conformations, their dynamic differences, and their relative preference for Type-I inhibitors such as gefitinib and Type-II inhibitors such as lapatinib. We discuss the implications of protein dynamics from a structure-based design perspective.

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Section: Protein Preparationmentioning

confidence: 99%

Computational study of EGFR inhibition: molecular dynamics studies on the active and inactive protein conformations

2012

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“…Similarly the relatively large size of HIV-1 RT has limited the number and scope of computational studies. Recently, studies have begun to emerge that probe NNRTI binding [28,29,30] and its impact on enzyme dynamics at the atomistic level. In particular molecular dynamics (MD) simulations by Ivetac and McCammon [29] have provided evidence to support the “arthritic thumb” hypothesis.…”

Section: Introductionmentioning

confidence: 99%

Global Conformational Dynamics of HIV-1 Reverse Transcriptase Bound to Non-Nucleoside Inhibitors

Wright

Hall

Kellam

et al. 2012

Biology

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HIV-1 Reverse Transcriptase (RT) is a multifunctional enzyme responsible for the transcription of the RNA genome of the HIV virus into DNA suitable for incorporation within the DNA of human host cells. Its crucial role in the viral life cycle has made it one of the major targets for antiretroviral drug therapy. The Non-Nucleoside RT Inhibitor (NNRTI) class of drugs binds allosterically to the enzyme, affecting many aspects of its activity. We use both coarse grained network models and atomistic molecular dynamics to explore the changes in protein dynamics induced by NNRTI binding. We identify changes in the flexibility and conformation of residue Glu396 in the RNaseH primer grip which could provide an explanation for the acceleration in RNaseH cleavage rate observed experimentally in NNRTI bound HIV-1 RT. We further suggest a plausible path for conformational and dynamic changes to be communicated from the vicinity of the NNRTI binding pocket to the RNaseH at the other end of the enzyme.

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“…Amber f99SB force field (Case et al, 2005;Lindorff-Larsen et al, 2010;Thomas et al, 2013) parameters were used for all residues and Gaff force field (Wang et al, 2006;Wang, Wolf, Caldwell, Kollman, & Case, 2004) The polar contribution is calculated using the Poisson-Boltzmann surface area model, while the non-polar energy is estimated from the solvent accessible surface area (SASA). The conformational entropy change (-TS) was computed by normal mode analysis from a set of conformational snapshots taken from the MD simulations (Hou et al, 2011;Kollman et al, 2000;Treesuwan & Hannongbua, 2009 …”

Section: Molecular Dynamics Simulationmentioning

confidence: 99%

Insights into molecular interactions between CaM and its inhibitors from molecular dynamics simulations and experimental data

González-Andrade

Rodríguez‐Sotres

Madariaga-Mazón

et al. 2015

Journal of Biomolecular Structure and Dynamics

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In order to contribute to the structural basis for rational design of calmodulin (CaM) inhibitors, we analyzed the interaction of CaM with 14 classic antagonists and two compounds that do not affect CaM, using docking and molecular dynamics (MD) simulations, and the data were compared to available experimental data. The Ca(2+)-CaM-Ligands complexes were simulated 20 ns, with CaM starting in the "open" and "closed" conformations. The analysis of the MD simulations provided insight into the conformational changes undergone by CaM during its interaction with these ligands. These simulations were used to predict the binding free energies (ΔG) from contributions ΔH and ΔS, giving useful information about CaM ligand binding thermodynamics. The ΔG predicted for the CaM's inhibitors correlated well with available experimental data as the r(2) obtained was 0.76 and 0.82 for the group of xanthones. Additionally, valuable information is presented here: I) CaM has two preferred ligand binding sites in the open conformation known as site 1 and 4, II) CaM can bind ligands of diverse structural nature, III) the flexibility of CaM is reduced by the union of its ligands, leading to a reduction in the Ca(2+)-CaM entropy, IV) enthalpy dominates the molecular recognition process in the system Ca(2+)-CaM-Ligand, and V) the ligands making more extensive contact with the protein have higher affinity for Ca(2+)-CaM. Despite their limitations, docking and MD simulations in combination with experimental data continue to be excellent tools for research in pharmacology, toward a rational design of new drugs.

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Bridge water mediates nevirapine binding to wild type and Y181C HIV-1 reverse transcriptase—Evidence from molecular dynamics simulations and MM-PBSA calculations

Cited by 24 publications

References 50 publications

Computational study of EGFR inhibition: molecular dynamics studies on the active and inactive protein conformations

Computational study of EGFR inhibition: molecular dynamics studies on the active and inactive protein conformations

Global Conformational Dynamics of HIV-1 Reverse Transcriptase Bound to Non-Nucleoside Inhibitors

Insights into molecular interactions between CaM and its inhibitors from molecular dynamics simulations and experimental data

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