In silico identification of BIM-1 (2-methyl-1H-indol-3-yl) as a potential therapeutic agent against elevated protein kinase C beta associated diseases

Abstract

Protein kinase C beta is involved in apoptosis, transcription regulation, B-cell activation, regulation of the B-cell receptor signalosome and B-cell survival by regulating BCR-induced NF-kappa-B activation. Increased activation of PKC-βI along with overproduction of diacylglycerol (DAG) and vascular endothelial growth factor (VEGF) participate in pathogenesis of various aliments like asthma, cancer propagation, cardiovascular disorders, diabetes, tumor formation, AIDS and neurological disturbances. Inhibiting elevated activation of PKC-βI, after identification of most appropriate inhibitor, could serve as a potential therapeutic option for the treatment of several diseases. Its computational modeling is important to study interactions with various other signaling proteins. The aim of study was to investigate computational model of protein kinase C- βI and inhibitory potential of BIM-1 (2-methyl-1H-indol-3-yl), balanol-1 and staurosporine-1 to protein kinase C- βI. Model of protein kinase C - βI was built with the assistance of Modeller software. Known structure of PKC-βII was compared with modeled protein. Template (PDB ID: 2I0E) was searched from PSI Blast and structural analysis was performed by using 3D Coffee. Quality of model was dependent on template and sequence alignment. Amidst the five generated models, quality factor of best selected model via ERRAT was obtained as 88.923. Using Auto Dock Tools, selected values were docked individually. After analysis of results in PyMOL 1.3 and SPDBV v4.02 viewer; on the basis of highest value of affinity (-8.6 kcal/mol), lower distance from root-mean-square deviation (RMSD) l.b (1.379) along-with four polar contacts with PKC-bI that is, [Glu101 (O-H=2.1 A), Val103 (O-N=2.9 A, O-O=3.3 A) and Thr84 (O-O=3.1 A)], BIM-1 was selected to the best inhibitor. This approach holds a great promise for understanding of PKC- βI inhibitors and consequently its role in therapeutics. Key words: Protein kinase C, protein kinase C beta, in silico, therapeutic agent, PRKCB1, PRKCB2, BIM-1 (2-methyl-1H-indol-3-yl), balanol-1 and staurosporine-1.