2D and 3D QSAR analyses to predict favorable substitution sites in anilino-monoindolylmaleimides acting as PKCβII selective inhibitors

• Published in: Medicinal chemistry research Vol. 20; no. 8; pp. 1188 - 1199
• Main Authors: Sri Divya, P., Grewal, Baljinder K., Elizabeth Sobhia, M.
• Format: Journal Article
• Language: English
• Published: New York Springer-Verlag 01.11.2011
• Subjects: Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell Biology; Original Research; Pharmacology/Toxicology; Diabetic cardiomyopathy; Fragments; PKCβII; HQSAR; CoMSIA
• ISSN: 1054-2523; 1554-8120
• DOI: 10.1007/s00044-010-9439-6

Diabetic cardiomyopathy (DCM) is a clinical condition, diagnosed when ventricular dysfunction develops in diabetic patients without coronary atherosclerosis and hypertension. Intensive studies on pathogenesis of DCM show PKCβII as one of the mediators, responsible for developing DCM. 2D-QSAR (HQSAR) and 3D-QSAR (CoMSIA) studies were performed on a dataset of 42 anilino-monoindolylmaleimides acting as PKCβII selective inhibitors. Among the different alignment strategies used for CoMSIA study FlexS was found to be the best alignment method. Conformational search was performed for a few molecules to obtain the best model. CoMSIA analysis gave information about sites of favorable substitutions and steered us to assume that alkyl amine substitution on the pharmacophore would be a favorable substituent for improving the biological activity. From HQSAR studies we could extrapolate the presence of tertiary acceptor group may probably be responsible for increase in the activity whereas occurrence of cyclic ring structures would lead to decrease in the activity.