Understanding the mechanisms of modulators’ action on enzymes is crucial for optimizing
and designing pharmaceutical substances. The acute inflammatory response, in particular, is regu lated mainly by a disintegrin and metalloproteinase (ADAM) 17. ADAM17 processes several disease
mediators such as TNFα and APP, releasing their soluble ectodomains (shedding). A malfunction
of this process leads to a disturbed inflammatory response. Chemical protease inhibitors such as
TAPI-1 were used in the past to inhibit ADAM17 proteolytic activity. However, due to ADAM170
s
broad expression and activity profile, the development of active-site-directed ADAM17 inhibitor was
discontinued. New ‘exosite’ (secondary substrate binding site) inhibitors with substrate selectivity
raised the hope of a substrate-selective modulation as a promising approach for inflammatory disease
therapy. This work aimed to develop a high-throughput screen for potential ADAM17 modula tors as therapeutic drugs. By combining experimental and in silico methods (structural modeling
and docking), we modeled the kinetics of ADAM17 inhibitor. The results explain ADAM17 inhibi tion mechanisms and give a methodology for studying selective inhibition towards the design of
pharmaceutical substances with higher selectivity
