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Application of Molecular Dynamics Simulations to the Design of Nucleotide Inhibitors Binding to Norovirus Polymerase.

ABSTRACT: The RNA-dependent RNA polymerase (RdRp) of norovirus is an attractive target of antiviral agents aimed at providing protection against norovirus-associated gastroenteritis. Here, we perform molecular dynamics simulations of the crystal structure of norovirus RdRp in complex with several known binders, as well as free-energy simulations by free-energy perturbation (FEP) to determine binding free energies of these molecules relative to the natural nucleotide substrates. We determine experimental EC₅₀ values and nucleotide incorporation efficiencies for several of these compounds. Moreover, we investigate the mechanism of inhibition of some of these ligands. Using FEP, we screened a virtual nucleotide library with 121 elements for binding to the polymerase and successfully identified two novel chain terminators.

SUBMITTER: Freedman H

PROVIDER: S-EPMC7869559 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Application of Molecular Dynamics Simulations to the Design of Nucleotide Inhibitors Binding to Norovirus Polymerase.

Freedman Holly H Kundu Juthika J Tchesnokov Egor Petrovitch EP Law John Lok Man JLM Nieman James A JA Schinazi Raymond F RF Tyrrell D Lorne DL Gotte Matthias M Houghton Michael M

Journal of chemical information and modeling 20201201 12

The RNA-dependent RNA polymerase (RdRp) of norovirus is an attractive target of antiviral agents aimed at providing protection against norovirus-associated gastroenteritis. Here, we perform molecular dynamics simulations of the crystal structure of norovirus RdRp in complex with several known binders, as well as free-energy simulations by free-energy perturbation (FEP) to determine binding free energies of these molecules relative to the natural nucleotide substrates. We determine experimental E ...[more]

PMID: 33259199

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Project description:Tyrosine threonine kinase (TTK) is the key component of the spindle assembly checkpoint (SAC) that ensures correct attachment of chromosomes to the mitotic spindle and thereby their precise segregation into daughter cells by phosphorylating specific substrate proteins. The overexpression of TTK has been associated with various human malignancies, including breast, colorectal and thyroid carcinomas. TTK has been validated as a target for drug development, and several TTK inhibitors have been discovered. In this study, ligand and structure-based alignment as well as various partial charge models were used to perform 3D-QSAR modelling on 1H-Pyrrolo[3,2-c] pyridine core containing reported inhibitors of TTK protein using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches to design better active compounds. Different statistical methods i.e., correlation coefficient of non-cross validation (r2), correlation coefficient of leave-one-out cross-validation (q2), Fisher's test (F) and bootstrapping were used to validate the developed models. Out of several charge models and alignment-based approaches, Merck Molecular Force Field (MMFF94) charges using structure-based alignment yielded highly predictive CoMFA (q2 = 0.583, Predr2 = 0.751) and CoMSIA (q2 = 0.690, Predr2 = 0.767) models. The models exhibited that electrostatic, steric, HBA, HBD, and hydrophobic fields play a key role in structure activity relationship of these compounds. Using the contour maps information of the best predictive model, new compounds were designed and docked at the TTK active site to predict their plausible binding modes. The structural stability of the TTK complexes with new compounds was confirmed using MD simulations. The simulation studies revealed that all compounds formed stable complexes. Similarly, MM/PBSA method based free energy calculations showed that these compounds bind with reasonably good affinity to the TTK protein. Overall molecular modelling results suggest that newly designed compounds can act as lead compounds for the optimization of TTK inhibitors.

Dataset Information

Application of Molecular Dynamics Simulations to the Design of Nucleotide Inhibitors Binding to Norovirus Polymerase.

Publications

Application of Molecular Dynamics Simulations to the Design of Nucleotide Inhibitors Binding to Norovirus Polymerase.

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