Computational simulation of ligand docking to L-type pyruvate kinase subunit

Kuznetsov, Aleksei; Faustova, Ilona; Järv, Jaak

doi:10.1016/j.compbiolchem.2013.10.006

Cited by 2 publications

(1 citation statement)

References 19 publications

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“…Conventional methods employ a single large box that covers the whole surface of the protein to search for putative binding sites. Conventional methods also use a rigid protein structure as the target for docking. − Although using a single box is adequate for small proteins where the spacing between the grid points is small enough to provide sufficient grid resolution for docking (given the fact that there is a maximum limit of 126 grid points for AUTODCOK − ), the same method does not work well for larger proteins. Here, we employed a new methodology, developed in-house, to account for the protein flexibility and to provide the highest grid resolution possible for the docking simulations.…”

Section: Discussionmentioning

confidence: 99%

A Refined Model of the HCV NS5A Protein Bound to Daclatasvir Explains Drug-Resistant Mutations and Activity against Divergent Genotypes

Barakat

Anwar-Mohamed

Tuszyński

et al. 2014

J. Chem. Inf. Model.

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Many direct-acting antiviral agents (DAAs) that selectively block hepatitis C virus (HCV) replication are currently under development. Among these agents is Daclatasvir, a first-in-class inhibitor targeting the NS5A viral protein. Although Daclatasvir is the most potent HCV antiviral molecule yet developed, its binding location and mode of binding remain unknown. The drug exhibits a low barrier to resistance mutations, particularly in genotype 1 viruses, but its efficacy against other genotypes is unclear. Using state-of-the-art modeling techniques combined with the massive computational power of Blue Gene/Q, we identified the atomic interactions of Daclatasvir within NS5A for different HCV genotypes and for several reported resistant mutations. The proposed model is the first to reveal the detailed binding mode of Daclatasvir. It also provides a tool to facilitate design of second generation drugs, which may confer less resistance and/or broader activity against HCV.

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Section: Discussionmentioning

confidence: 99%

A Refined Model of the HCV NS5A Protein Bound to Daclatasvir Explains Drug-Resistant Mutations and Activity against Divergent Genotypes

Barakat

Anwar-Mohamed

Tuszyński

et al. 2014

J. Chem. Inf. Model.

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Roadmap to Pyruvate Kinase M2 Modulation - A Computational Chronicle

Kapoor

Chatterjee

Chowdhury

et al. 2023

CDT

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Pyruvate kinase M2 (PKM2) has surfaced as a potential target for anti-cancer therapy. PKM2 is known to be overexpressed in the tumor cells and is a critical metabolic conduit in supplying the augmented bioenergetic demands of the recalcitrant cancer cells. The presence of PKM2 in structurally diverse tetrameric as well as dimeric forms has opened new avenues to design novel modulators. It is also a truism to state that drug discovery has advanced significantly from various computational techniques like molecular docking, virtual screening, molecular dynamics, and pharmacophore mapping. The present review focuses on the role of computational tools in exploring novel modulators of PKM2. The structural features of various isoforms of PKM2 have been discussed along with reported modulators. An extensive analysis of the structure-based and ligand-based in silico methods aimed at PKM2 modulation has been conducted with an in-depth review of the literature. The role of advanced tools like QSAR and quantum mechanics has been established with a brief discussion of future perspectives.

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Computational simulation of ligand docking to L-type pyruvate kinase subunit

Cited by 2 publications

References 19 publications

A Refined Model of the HCV NS5A Protein Bound to Daclatasvir Explains Drug-Resistant Mutations and Activity against Divergent Genotypes

A Refined Model of the HCV NS5A Protein Bound to Daclatasvir Explains Drug-Resistant Mutations and Activity against Divergent Genotypes

Roadmap to Pyruvate Kinase M2 Modulation - A Computational Chronicle

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