Molecular dynamics simulations and MM/GBSA methods to investigate binding mechanisms of aminomethylpyrimidine inhibitors with DPP-IV

Gao, Jian; Yang, Cheng; Cui, Wei; Zhang, Huai; Ji, Mingjuan

doi:10.1016/j.bmcl.2011.09.093

Cited by 16 publications

(9 citation statements)

References 33 publications

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“…In the present study, we have calculated the occupancy percentages of hydrogen bonds that more than 10% for all complexes during MD simulations. Based on the occupancy percentages, a hydrogen bond is considered to be stable when the occupancy is more than 50% [ 26 ]. The results showed that only two compounds, i.e., ZINC16525481, and ZINC38484632, which formed stable hydrogen bonds in their complex with EGFR and VEGFR2 as presented in Table 3 .…”

Section: Resultsmentioning

confidence: 99%

Ligand-Based Pharmacophore Modeling, Molecular Docking, and Molecular Dynamic Studies of Dual Tyrosine Kinase Inhibitor of EGFR and VEGFR2

Sangande

Julianti

Tjahjono

2020

IJMS

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Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR2) play an important role in cancer growth. Both of them have close relationships. Expression of EGFR will induce an angiogenic factor (VEGF) release for binding with VEGFR2. However, the existence of VEGF up-regulation independent of EGFR leads to cancer cell resistance to anti-EGFR. Therefore, a therapeutic approach targeting EGFR and VEGFR2 simultaneously may improve the outcome of cancer treatment. The present study was designed to identify potential compounds as a dual inhibitor of EGFR and VEGFR2 by the computational method. Firstly, the ligand-based pharmacophore model for each target was setup to screen of ZINC database of purchasable compounds. The hit compounds obtained by pharmacophore screening were then further screened by molecular docking studies. Taking erlotinib (EGFR inhibitor) and axitinib (VEGFR2 inhibitor) as reference drugs, six potential compounds (ZINC08398597, ZINC12047553, ZINC16525481, ZINC17418102, ZINC21942954, and ZINC38484632) were selected based on their docking scores and binding interaction. However, molecular dynamics simulations demonstrated that only ZINC16525481 and ZINC38484632 which have good binding free energy and stable hydrogen bonding interactions with EGFR and VEGFR2. The result represents a promising starting point for developing potent dual tyrosine kinases inhibitor of EGFR and VEGFR2.

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Section: Resultsmentioning

confidence: 99%

Ligand-Based Pharmacophore Modeling, Molecular Docking, and Molecular Dynamic Studies of Dual Tyrosine Kinase Inhibitor of EGFR and VEGFR2

Sangande

Julianti

Tjahjono

2020

IJMS

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“…Despite the approximations inherent to MMGBSA decomposition, it was shown to be useful for explaining the relative importance of interactions between enzymes and ligands (see, e.g. , Refs 89–91…”

Section: Discussionmentioning

confidence: 99%

Comparing aminoglycoside binding sites in bacterial ribosomal RNA and aminoglycoside modifying enzymes

2012

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Aminoglycoside antibiotics are used against severe bacterial infections. They bind to the bacterial ribosomal RNA and interfere with the translation process. However, bacteria produce aminoglycoside modifying enzymes (AME) to resist aminoglycoside actions. AMEs form a variable group and yet they specifically recognize and efficiently bind aminoglycosides, which are also diverse in terms of total net charge and the number of pseudo-sugar rings. Here, we present the results of 25 molecular dynamics simulations of three AME representatives and aminoglycoside ribosomal RNA binding site, unliganded and complexed with an aminoglycoside, kanamycin A. A comparison of the aminoglycoside binding sites in these different receptors revealed that the enzymes efficiently mimic the nucleic acid environment of the ribosomal RNA binding cleft. Although internal dynamics of AMEs and their interaction patterns with aminoglycosides differ, the energetical analysis showed that the most favorable sites are virtually the same in the enzymes and RNA. The most copied interactions were of electrostatic nature, but stacking was also replicated in one AME:kanamycin complex. In addition, we found that some water-mediated interactions were very stable in the simulations of the complexes. We show that our simulations reproduce well findings from NMR or X-ray structural studies, as well as results from directed mutagenesis. The outcomes of our analyses provide new insight into aminoglycoside resistance mechanism that is related to the enzymatic modification of these drugs.

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“…After relaxation, each system was gradually heated from 0 to 300 K in 15 ps and then maintained at 300 K for 35 ps. 54 Following the equilibration procedure, 2000 ps MD simulations were performed with a periodic boundary condition in the NPT ensemble, where the temperature (300 K) and constant pressure (1 atm) were maintained by Berendsen temperature coupling with a time constant of 1.0 ps and isotropic position scaling with a relaxation time of 2.0 ps, respectively. To observe the equilibration, root mean square deviations (RMSD) were recorded for all systems.…”

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confidence: 99%

Role of a remote leucine residue in the catalytic function of polyol dehydrogenase

Tiwari¹,

Kalia

Lee³

2014

Mol. BioSyst.

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Studies on the protein-metal binding sites have mainly focused on the residues immediately surrounding the reacting substrate, cofactors, and metal ions. The contribution of residues in remote layers to the highly optimized microenvironments of catalytic active sites is not well understood. To improve our understanding, the present study examined the role of remote residues on the structure and function of zinc-dependent polyol dehydrogenases. We used an integrated computational and biochemical approach to determine the role of L136 in the third shell of the l-arabinitol 4-dehydrogenase (LAD) from Neurospora crassa. Substitution of L136 with charged (Asp, Lys, or His) and bulky (Trp) side chain amino acids abolished enzyme activity. Whereas the L136A mutant exhibited a 95% decrease in catalytic efficiency (kcat/Km), the L136C mutant exhibited a 39% decrease in kcat/Km. Additionally, molecular docking and dynamic simulations on the mutant (L136A, L136C, L136H, and L136P) complexes showed the loss of crucial H-bonds between G77 and the corresponding mutated residue. It is evident from theoretical and biochemical studies that the L136 is part of the extensive hydrogen bonding network coupled to the reaction catalyzed at the active site. We propose that L136, critically positioned behind the active site residues H78 and E79 in the third shell of LAD, plays a crucial role in modulating catalysis or substrate binding by stabilizing the GHE motif in the LAD active site.

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Molecular dynamics simulations and MM/GBSA methods to investigate binding mechanisms of aminomethylpyrimidine inhibitors with DPP-IV

Cited by 16 publications

References 33 publications

Ligand-Based Pharmacophore Modeling, Molecular Docking, and Molecular Dynamic Studies of Dual Tyrosine Kinase Inhibitor of EGFR and VEGFR2

Ligand-Based Pharmacophore Modeling, Molecular Docking, and Molecular Dynamic Studies of Dual Tyrosine Kinase Inhibitor of EGFR and VEGFR2

Comparing aminoglycoside binding sites in bacterial ribosomal RNA and aminoglycoside modifying enzymes

Role of a remote leucine residue in the catalytic function of polyol dehydrogenase

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