Pharmacophore-based 3DQSAR and molecular docking studies to identify new non-peptidic inhibitors of cathepsin S

Cathepsin S (CatS) is one of the 11 cysteine protease cathepsins which are expressed predominantly in antigen presenting cells (APC) namely B cells, macrophages and dendritic cells. CatS has been implicated in a wide range of diseases such as rheumatoid arthritis, multiple sclerosis, neuropathic pain and allergic disorders. In the present study, pharmacophore mapping studies followed by 3D QSAR analysis was undertaken for a large set of 161 molecules reported to be non-covalent binding and non-peptidic inhibitors of CatS. The activity range (IC50) of these compounds was between 2 picomolar to 100 nanomolar. A five point pharmacophore model with three hydrogen bond acceptors (A), one hydrogen bond donor (D) and one hydrophobic (H) group as pharmacophoric features was developed. The generated model showed reasonable predictive power, with a correlation coefficient Q(2) of 0.607. The model was further confirmed by an external test-set validation that showed statistically significant parameters r(2) value of 0.840 with the R(2)p value of 0.812 and r(2)m value of 0.530. Validated model was then used to identify six diverse non-peptidic scaffolds from a commercial structure database by the analyses of parameters such as pharmacophore fitness, docking score, interacting amino acids and ADME properties to achieve prototypical lead compounds.