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Active site fingerprinting and pharmacophore screening strategies for the identification of dual inhibitors of protein kinase C (ΡΚCβ) and poly (ADP-ribose) polymerase-1 (PARP-1).
Mol Divers. 2016 08; 20(3):747-61.MD

Abstract

Current clinical studies have revealed that diabetic complications are multifactorial disorders that target two or more pathways. The majority of drugs in clinical trial target aldose reductase and protein kinase C ([Formula: see text]), while recent studies disclosed a significant role played by poly (ADP-ribose) polymerase-1 (PARP-1). In light of this, the current study was aimed to identify novel dual inhibitors of [Formula: see text] and PARP-1 using a pharmaco-informatics methodology. Pharmacophore-based 3D QSAR models for these two targets were generated using HypoGen and used to screen three commercially available chemical databases to identify dual inhibitors of [Formula: see text] and PARP-1. Overall, 18 hits were obtained from the screening process; the hits were filtered based on their drug-like properties and predicted binding affinities (docking analysis). Important amino acid residues were predicted by developing a fingerprint of the active site using alanine-scanning mutagenesis and molecular dynamics. The stability of the complexes (18 hits with both proteins) and their final binding orientations were investigated using molecular dynamics simulations. Thus, novel hits have been predicted to have good binding affinities for [Formula: see text] and PARP-1 proteins, which could be further investigated for in vitro/in vivo activity.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Chadha N
Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, 147002, India.
Silakari O
Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, 147002, India. omsilakari@gmail.com.

MeSH

AlgorithmsCatalytic DomainDatabases, ChemicalDrug DesignEnzyme InhibitorsModels, ChemicalMolecular Docking SimulationPoly (ADP-Ribose) Polymerase-1Protein Kinase CQuantitative Structure-Activity Relationship

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27216445

Citation

Chadha, Navriti, and Om Silakari. "Active Site Fingerprinting and Pharmacophore Screening Strategies for the Identification of Dual Inhibitors of Protein Kinase C (ΡΚCβ) and Poly (ADP-ribose) Polymerase-1 (PARP-1)." Molecular Diversity, vol. 20, no. 3, 2016, pp. 747-61.
Chadha N, Silakari O. Active site fingerprinting and pharmacophore screening strategies for the identification of dual inhibitors of protein kinase C (ΡΚCβ) and poly (ADP-ribose) polymerase-1 (PARP-1). Mol Divers. 2016;20(3):747-61.
Chadha, N., & Silakari, O. (2016). Active site fingerprinting and pharmacophore screening strategies for the identification of dual inhibitors of protein kinase C (ΡΚCβ) and poly (ADP-ribose) polymerase-1 (PARP-1). Molecular Diversity, 20(3), 747-61. https://doi.org/10.1007/s11030-016-9676-9
Chadha N, Silakari O. Active Site Fingerprinting and Pharmacophore Screening Strategies for the Identification of Dual Inhibitors of Protein Kinase C (ΡΚCβ) and Poly (ADP-ribose) Polymerase-1 (PARP-1). Mol Divers. 2016;20(3):747-61. PubMed PMID: 27216445.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Active site fingerprinting and pharmacophore screening strategies for the identification of dual inhibitors of protein kinase C (ΡΚCβ) and poly (ADP-ribose) polymerase-1 (PARP-1). AU - Chadha,Navriti, AU - Silakari,Om, Y1 - 2016/05/23/ PY - 2015/11/10/received PY - 2016/05/09/accepted PY - 2016/5/25/entrez PY - 2016/5/25/pubmed PY - 2017/3/10/medline KW - Alanine-scanning mutagenesis KW - Diabetic complications KW - Molecular dynamics KW - PARP inhibitor KW - Quantitative structure–activity relationship KW - Virtual screening KW - inhibitor SP - 747 EP - 61 JF - Molecular diversity JO - Mol Divers VL - 20 IS - 3 N2 - Current clinical studies have revealed that diabetic complications are multifactorial disorders that target two or more pathways. The majority of drugs in clinical trial target aldose reductase and protein kinase C ([Formula: see text]), while recent studies disclosed a significant role played by poly (ADP-ribose) polymerase-1 (PARP-1). In light of this, the current study was aimed to identify novel dual inhibitors of [Formula: see text] and PARP-1 using a pharmaco-informatics methodology. Pharmacophore-based 3D QSAR models for these two targets were generated using HypoGen and used to screen three commercially available chemical databases to identify dual inhibitors of [Formula: see text] and PARP-1. Overall, 18 hits were obtained from the screening process; the hits were filtered based on their drug-like properties and predicted binding affinities (docking analysis). Important amino acid residues were predicted by developing a fingerprint of the active site using alanine-scanning mutagenesis and molecular dynamics. The stability of the complexes (18 hits with both proteins) and their final binding orientations were investigated using molecular dynamics simulations. Thus, novel hits have been predicted to have good binding affinities for [Formula: see text] and PARP-1 proteins, which could be further investigated for in vitro/in vivo activity. SN - 1573-501X UR - https://www.unboundmedicine.com/medline/citation/27216445/Active_site_fingerprinting_and_pharmacophore_screening_strategies_for_the_identification_of_dual_inhibitors_of_protein_kinase_C__ΡΚCβ__and_poly__ADP_ribose__polymerase_1__PARP_1__ DB - PRIME DP - Unbound Medicine ER -