Abstract
Protein Kinase C βII (PKCβII) overexpression has been linked to various diabetic microvascular complications viz. retinopathy, neuropathy, and cardiomyopathy. Novel and potent small molecules with preferential selective inhibitory property of PKCβII will be helpful in treatment as well as understanding insight of PKCβII involvement in these complications. Robust 3D hypotheses were developed using both the crystal structure and available PKCβII ligands, and were validated by feature mapping and screening in-house database of reported PKCβII compounds. The best hypothesis from both methods consists of six features viz. one hydrogen bond donor (D), two hydrogen bond acceptors (A1, A2), two hydrophobic-aromatics (H1, H2) and one ring aromatic (R). A synergistic approach of virtual screening using both ligand and receptor based pharmacophore model was used for the flexible search of ligands from chemical databases. The hits obtained were screened by molecular docking and their binding affinity was predicted using MMPBSA calculations. The first receptor based query of PKCβII and new scaffold of its inhibitors with good estimated activities, favorable binding interactions, and high docking score were identified.
Keywords: Molecular docking, molecular dynamics, pharmacophore modeling, PKCβII inhibitors, scaffold, virtual screening.
Combinatorial Chemistry & High Throughput Screening
Title:Scaffold Hopping for Identification of Novel PKCβII Inhibitors Based on Ligand and Structural Approaches, Virtual Screening and Molecular Dynamics Study
Volume: 17 Issue: 1
Author(s): Baljinder K. Grewal and Masilamani E. Sobhia
Affiliation:
Keywords: Molecular docking, molecular dynamics, pharmacophore modeling, PKCβII inhibitors, scaffold, virtual screening.
Abstract: Protein Kinase C βII (PKCβII) overexpression has been linked to various diabetic microvascular complications viz. retinopathy, neuropathy, and cardiomyopathy. Novel and potent small molecules with preferential selective inhibitory property of PKCβII will be helpful in treatment as well as understanding insight of PKCβII involvement in these complications. Robust 3D hypotheses were developed using both the crystal structure and available PKCβII ligands, and were validated by feature mapping and screening in-house database of reported PKCβII compounds. The best hypothesis from both methods consists of six features viz. one hydrogen bond donor (D), two hydrogen bond acceptors (A1, A2), two hydrophobic-aromatics (H1, H2) and one ring aromatic (R). A synergistic approach of virtual screening using both ligand and receptor based pharmacophore model was used for the flexible search of ligands from chemical databases. The hits obtained were screened by molecular docking and their binding affinity was predicted using MMPBSA calculations. The first receptor based query of PKCβII and new scaffold of its inhibitors with good estimated activities, favorable binding interactions, and high docking score were identified.
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Grewal K. Baljinder and Sobhia E. Masilamani, Scaffold Hopping for Identification of Novel PKCβII Inhibitors Based on Ligand and Structural Approaches, Virtual Screening and Molecular Dynamics Study, Combinatorial Chemistry & High Throughput Screening 2014; 17 (1) . https://dx.doi.org/10.2174/1386207311301010008
DOI https://dx.doi.org/10.2174/1386207311301010008 |
Print ISSN 1386-2073 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5402 |
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