Scaffold Hopping for Identification of Novel PKCβII Inhibitors Based on Ligand and Structural Approaches, Virtual Screening and Molecular Dynamics Study

Baljinder   K.   Grewal; Masilamani   E.   Sobhia

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.

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