Dataset Information

Molecular Analysis and Modeling of Hepatitis E Virus Helicase and Identification of Novel Inhibitors by Virtual Screening.

ABSTRACT: The hepatitis E virus- (HEV-) helicase as a novel drug-target was evaluated. While cell culture model was used for mutational characterization of helicase, in silico protein modeling and virtual screening were employed to identify helicase inhibitors. None of the saturation mutant replicons significantly affected RNA replication. Notably, mutants encompassing the Walker motifs replicated as wild-type, showing indispensability of nucleotides conservation in viability compared to known criticality of amino acids. A 3D modeling of HEV-helicase and screening of a compound dataset identified ten most promising inhibitors with drug likeness, notably, JFD02650, RDR03130, and HTS11136 that interacted with Walker A residues Gly975, Gly978, Ser979, and Gly980. Our model building and virtual identification of novel helicase inhibitors warrant further studies towards developing anti-HEV drugs.

SUBMITTER: Parvez MK

PROVIDER: S-EPMC6136533 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Molecular Analysis and Modeling of Hepatitis E Virus Helicase and Identification of Novel Inhibitors by Virtual Screening.

Parvez Mohammad K MK Subbarao Naidu N

BioMed research international 20180830

The hepatitis E virus- (HEV-) helicase as a novel drug-target was evaluated. While cell culture model was used for mutational characterization of helicase, <i>in silico</i> protein modeling and virtual screening were employed to identify helicase inhibitors. None of the saturation mutant replicons significantly affected RNA replication. Notably, mutants encompassing the Walker motifs replicated as wild-type, showing indispensability of nucleotides conservation in viability compared to known crit ...[more]

PMID: 30246023

Similar Datasets

Project description:Cyclophilin D (CypD) is a peptidyl prolyl isomerase F that resides in the mitochondrial matrix and associates with the inner mitochondrial membrane during the mitochondrial membrane permeability transition. CypD plays a central role in opening the mitochondrial membrane permeability transition pore (mPTP) leading to cell death and has been linked to Alzheimer's disease (AD). Because CypD interacts with amyloid beta (Aβ) to exacerbate mitochondrial and neuronal stress, it is a potential target for drugs to treat AD. Since appropriately designed small organic molecules might bind to CypD and block its interaction with Aβ, 20 trial compounds were designed using known procedures that started with fundamental pyrimidine and sulfonamide scaffolds know to have useful therapeutic effects. Two-dimensional (2D) quantitative structure-activity relationship (QSAR) methods were applied to 40 compounds with known IC50 values. These formed a training set and were followed by a trial set of 20 designed compounds. A correlation analysis was carried out comparing the statistics of the measured IC50 with predicted values for both sets. Selectivity-determining descriptors were interpreted graphically in terms of principle component analyses. These descriptors can be very useful for predicting activity enhancement for lead compounds. A 3D pharmacophore model was also created. Molecular dynamics simulations were carried out for the 20 trial compounds with known IC50 values, and molecular descriptors were determined by 2D QSAR studies using the Lipinski rule-of-five. Fifteen of the 20 molecules satisfied all 5 Lipinski rules, and the remaining 5 satisfied 4 of the 5 Lipinski criteria and nearly satisfied the fifth. Our previous use of 2D QSAR, 3D pharmacophore models, and molecular docking experiments to successfully predict activity indicates that this can be a very powerful technique for screening large numbers of new compounds as active drug candidates. These studies will hopefully provide a basis for efficiently designing and screening large numbers of more potent and selective inhibitors for CypD treatment of AD.

Dataset Information

Molecular Analysis and Modeling of Hepatitis E Virus Helicase and Identification of Novel Inhibitors by Virtual Screening.

Publications

Molecular Analysis and Modeling of Hepatitis E Virus Helicase and Identification of Novel Inhibitors by Virtual Screening.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets