QSAR study of 1,3–dioxo-4-methyl-2,3-dihydro-1h-pyrrolo[3,4-c]quinolines as caspase-3 inhibitors

• Published in: Medicinal chemistry research 2008-06, Vol.17 (2-7), p.399-411
• Main Authors: Sharma, Simant, Sahu, Kamlesh, Jain, Prateek, Mourya, V. K., Agrawal, Ram K.
• Format: Article
• Language: English
• Subjects: Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell Biology; Original Research; Pharmacology/Toxicology
• ISSN: 1054-2523; 1554-8120
• DOI: 10.1007/s00044-007-9075-y

Neurodegenerative disorders are consequences of progressive and irreversible loss of neurons due to unwanted apoptosis, which involves caspases, a group of cystein proteases that cleave other proteins and inactivate them. Among several different groups of caspase enzymes, caspases-3 play a key role in apoptosis. Therefore they are used as therapeutic target for their inhibitors. In pursuit of better caspase-3 inhibitors, a quantitative structure–activity relationship analysis was performed on a series of 1,3-dioxo-4-methyl-2, 3-dihydro-1H-pyrrolo [3,4-c] quinolines as caspase-3 inhibitors using WIN CAChe 6.1 and Medicinal Chemistry Regression Machine. The best QSAR model was selected and validated. The values of the statistical data are r  = 0.951, F  = 65.62, SEE = 0.4175, t  = 2.08. The study reveals that, if the partition coefficient (log P ), conformational minimum energy (CME), and the lowest unoccupied molecular orbital energy ( E LUMO ) are altered, the biological activity is increased. On the basis of the selected QSAR model, we designed a new series of compounds, calculated their activity, and found that the compounds were more potent than existing compounds.