Binding mechanism of selective cathepsin K/S inhibition revealed from molecular simulations

Cathepsin K and S are two isoforms of cysteine protease with diverse biological functions in the aspect osteoporosis autoimmune diseases. Accordingly, homologous sequence similar binding site features among CTSK/S may lead to unselective inhibition side effects. To address such issue, various computational strategies were applied current study explore selectivity mechanism inhibitors, including alignment, molecular docking, MD simulations, MM/GBSA energy calculation, so on. Our findings highlight notable effects CTSK residues Glu59 Tyr67, as well CTSS residue Asn67, on selectivity. Overall, this provides an informative guideline for rational design selective inhibitors.