In search of selective 11β-HSD type 1 inhibitors without nephrotoxicity: An approach to resolve the metabolic syndrome by virtual based screening

Over expression of 11β-HSD 1 in key metabolic tissues is related to the development of type 2 diabetes, obesity, hypertension and metabolic syndrome. Nephrotoxicity of corosolic acid (selective inhibitor of 11β-HSD 1) is recently reported, which is one of the major drawback. Therefore, it is of great interest to find out the selective 11β-HSD 1 inhibitors without nephrotoxicity. Using crystal structures of 11β-HSD 1 in complex with inhibitors as a source of structural information, a combined structure-based virtual screening approach followed by PASS toxicity prediction, Lipinski’s rule and ADME prediction was implemented to find out the potent and selective 11 β-HSD 1 analog of corosolic acid without nephrotoxicity. Two compounds with NCBI compound identification number CID59752459 (Genins of Asiatic acid) and CID 119034 (Asiatic acid) were found to be selective for the 11β-HSD 1 enzyme without nephrotoxicity which comply with Lipinski’s rule and ADME parameter defined for human use. However, none of the hits inhibited 11β-HSD 2 at 100 μM indicating their selectivity against 11β-HSD 1

In search of selective 11β-HSD type 1 inhibitors without nephrotoxicity: An approach to resolve the metabolic syndrome by virtual based screening

AbstractOver expression of 11β-HSD 1 in key metabolic tissues is related to the development of type 2 diabetes, obesity, hypertension and metabolic syndrome. Nephrotoxicity of corosolic acid (selective inhibitor of 11β-HSD 1) is recently reported, which is one of the major drawback. Therefore, it is of great interest to find out the selective 11β-HSD 1 inhibitors without nephrotoxicity. Using crystal structures of 11β-HSD 1 in complex with inhibitors as a source of structural information, a combined structure-based virtual screening approach followed by PASS toxicity prediction, Lipinski’s rule and ADME prediction was implemented to find out the potent and selective 11 β-HSD 1 analog of corosolic acid without nephrotoxicity. Two compounds with NCBI compound identification number CID59752459 (Genins of Asiatic acid) and CID 119034 (Asiatic acid) were found to be selective for the 11β-HSD 1 enzyme without nephrotoxicity which comply with Lipinski’s rule and ADME parameter defined for human use. However, none of the hits inhibited 11β-HSD 2 at 100μM indicating their selectivity against 11β-HSD 1