QSAR Studies on keto sulfones derivatives as inhibitors of 11β-hydroxysteroid dehydrogenase type 1
By Shashank Trivedi, Prakash C. Patidar, Pradeep K. Chaurasiya, Rajesh S. Pawar, Umesh K. Patil and Pradeep K. Singour
Metabolic disorders, such as obesity and type 2 diabetes, have assumed epidemic proportions and present major challenges for healthcare systems. The keto sulfones derivatives were discovered as potent and selective 11β-HSD1 inhibitors. The studies show that these compounds are not active against 11β-HSD2 and thus easily surpass the side effects of inhibition of 11β-HSD2 such as sodium retention, hypokalemia and hypertension. So here we have tried to explore the series of β- keto sulfones derivatives, to develop novel, selective and potent orally active compounds through QSAR analysis. The QSAR study carried out on 23 keto sulfones derivatives as inhibitors of 11β-HSD. Molecular modeling studies were performed using chemoffice 6.0 supplied by cambridgesoft. The sketched structures were subjected to energy minimization & the lowest energy structure was used to calculate the physiochemical properties. The regression analysis was carried out using a computer program called SYSTAT 10.2. The best models were selected from the various statistically significant equations. The study revealed that the LUMO, Dipole-dipole energy, NVDW contributed positively, and Heat of formation contributed negatively. The analysis resulted in 2-D equation, which suggests that, n=16, r=0.953, r2=0.909, Standard error of estimate(s)=0.342 & validated r2(q2) =0.7135. This study can help in rational drug design and synthesis of new selective 11β-HSD1 with predetermined affinity.
Key words: HSD1; 11β-HSD1; diabetes; metabolic syndrome; keto sulfones derivatives; QSAR.