Identification of specific features of inhibition of PKCβII and its potential lead by shape-based virtual screening and molecular docking studies

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 14; pp. 4672 - 4677
• Main Authors: Grewal, Baljinder K., Elizabeth Sobhia, M.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.07.2012; Elsevier
• Subjects: binding capacity; Biological and medical sciences; cardiomyopathy; Diabetic cardiomyopathy; diabetic complications; Drug Evaluation, Preclinical; Drug-design; drugs; filters; filtration; Maleimide moiety; Medical sciences; Models, Molecular; molecular dynamics; Molecular-docking; Pharmacology. Drug treatments; PKCβII-inhibitors; Protein Interaction Domains and Motifs; protein kinase C; Protein Kinase C - antagonists & inhibitors; Protein Kinase Inhibitors - chemistry; Rational design; screening; toxicity; Diabetic cardiomyopathy; Molecular-docking; Maleimide moiety; Rational design; Drug-design; PKCβII-inhibitors; Endocrinopathy; Drug; Cardiomyopathy; Diabetes mellitus; Virtual screening; Cardiovascular disease; Molecular interaction; Myocardial disease; Modeling; Imide; Structure activity relation; Heart disease; Molecular model; Docking; Complication; Inhibitor; Inhibition
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.05.085

The graphical representation highlights the important pharmacophoric features of the ligand to enhance the PKCβII inhibition. Protein kinase C βII (PKCβII) is preferentially expressed during hyperglycemic state resulting in diabetic complications, particularly, diabetic cardiomyopathy. An effective inhibition of PKCβII is a potential option to directly treat the diabetic cardiomyopathy; however, till date no efficient drug targeting PKCβII is available and all the reported PKCβII ligands are maleimide derivatives. The purpose of the present work is to study the importance of the maleimide moiety in PKCβII inhibition and the effects that follow after replacing the maleimide with similar moiety on PKCβII inhibition. For this, an in-house database of maleimide analogues was prepared and shape based screening of commercial databases viz. Specs2009, NCI2003 was performed, followed by filtration using virtual filters. The binding features of reported PKCβII inhibitors, and high scoring hits were analyzed with the help of molecular docking studies. The features identified from the above studies were used for the rational design of new PKCβII inhibitors. The molecular dynamics simulation and ligand–receptor binding affinity studies of the designed molecules has been reported. The toxicity of all the shortlisted and designed molecules was predicted.