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 Q2 of 0.607. The model was further confirmed by an external
test-set validation that showed statistically significant parameters r2 value of 0.840with the R2p value of 0.812 and r2m 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.
Keywords: Cathepsin S, pharmacophore modeling, 3D QSAR, virtual screening, pharmacokinetics.
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