Please use this identifier to cite or link to this item: doi:10.22028/D291-35476
Title: In Silico and Experimental ADAM17 Kinetic Modeling as Basis for Future Screening System for Modulators
Author(s): Bienstein, Marian
Minond, Dmitriy
Schwaneberg, Ulrich
Davari, Mehdi D.
Yildiz, Daniela
Language: English
Title: International Journal of Molecular Sciences
Volume: 23
Issue: 3
Publisher/Platform: MDPI
Year of Publication: 2022
Free key words: ADAM17
molecular docking
kinetic modelling
exosite inhibitors
inhibitor design
reaction mechanism
DDC notations: 610 Medicine and health
Publikation type: Journal Article
Abstract: 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.
DOI of the first publication: 10.3390/ijms23031368
Link to this record: urn:nbn:de:bsz:291--ds-354760
ISSN: 1422-0067
Date of registration: 17-Feb-2022
Description of the related object: Supplementary Materials
Related object:
Faculty: M - Medizinische Fakultät
Department: M - Experimentelle und Klinische Pharmakologie und Toxikologie
Professorship: M - Jun.-Prof. Dr. Daniela Yildiz
Collections:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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