In this paper we describe the procedure of allosteric site prediction in papain-like cysteine peptidases by computational methods, using cathepsin K as the model enzyme. Compound libraries were screened in silico to identify compound NSC13345 as the first low-molecular-weight allosteric inhibitor of cathepsin K. THe compound was thoroughly characterized from the functional and structural perspectives. The crystal structure of the cathepsin K/NSC13345 complex showed that the compound indeed binds at the computationally anticipated site, which was thereby identified as a novel allosteric site in cathepsin K. The compound was characterized as a partial inhibitor of the hydrolysis of synthetic substrates and azocasein and a full inhibitor of type I collagen hydrolysis. These results qualify compound NSC1334 as an excellent candidate for the design of drugs for the treatment of osteoporosis.
COBISS.SI-ID: 1678895
Review article on the biochemical properties and physiological and pathological roles of cathepsin K, as well as the development of inhibitors for the treatment of osteoporosis.
COBISS.SI-ID: 1606191
Review article on the family of papain-like cysteine peptidases, which discusses their biochemical and physiological roles from the perspective of the evolutionary lineages of the family.
COBISS.SI-ID: 36659717