2. Academic Validation
  3. In Silico and Experimental ADAM17 Kinetic Modeling as Basis for Future Screening System for Modulators

In Silico and Experimental ADAM17 Kinetic Modeling as Basis for Future Screening System for Modulators

  • Int J Mol Sci. 2022 Jan 25;23(3):1368. doi: 10.3390/ijms23031368.
Marian Bienstein 1,  Dmitriy Minond 2 3,  Ulrich Schwaneberg 1 4,  Mehdi D Davari 5,  Daniela Yildiz 6
Affiliations

Affiliations

  • 1 Institute of Biotechnology, RWTH Aachen University, Worringerweg 3, 52074 Aachen, Germany.
  • 2 College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33314, USA.
  • 3 Rumbaugh-Goodwin Institute for Cancer Research, Nova Southeastern University, Fort Lauderdale, FL 33314, USA.
  • 4 DWI-Leibniz Institute for Interactive Materials, Forckenbeckstraße 50, 52056 Aachen, Germany.
  • 5 Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, 06120 Halle, Germany.
  • 6 Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Center for Human and Molecular Biology (ZHMB), University of Saarland, Kirrbergerstr., 66421 Homburg, Germany.
PMID: 35163294 DOI: 10.3390/ijms23031368
Abstract

Understanding the mechanisms of modulators' action on enzymes is crucial for optimizing and designing pharmaceutical substances. The acute inflammatory response, in particular, is regulated 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 ADAM17'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 modulators 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 inhibition mechanisms and give a methodology for studying selective inhibition towards the design of pharmaceutical substances with higher selectivity.

Keywords

ADAM17; biocatalysis; exosite inhibitors; inhibitor design; kinetic modelling; metalloproteinases; molecular docking; reaction mechanism.

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