2. Academic Validation
  3. Design of MMP-1 inhibitors via SAR transfer and experimental validation

Design of MMP-1 inhibitors via SAR transfer and experimental validation

  • Sci Rep. 2022 Dec 3;12(1):20915. doi: 10.1038/s41598-022-25079-4.
Kohei Umedera 1,  Atsushi Yoshimori 2,  Jürgen Bajorath # 3,  Hiroyuki Nakamura # 4 5
Affiliations

Affiliations

  • 1 School of Life Science and Technology, Tokyo Institute of Technology, 4259, Nagatsuta-Cho, Midori-Ku, Yokohama, 226-8503, Japan.
  • 2 Institute for Theoretical Medicine, Inc., 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan.
  • 3 Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Friedrich-Hirzebruch-Allee 5/6, 53115, Bonn, Germany. bajorath@bit.uni-bonn.de.
  • 4 School of Life Science and Technology, Tokyo Institute of Technology, 4259, Nagatsuta-Cho, Midori-Ku, Yokohama, 226-8503, Japan. hiro@res.titech.ac.jp.
  • 5 Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, 4259, Nagatsuta-Cho, Midori-Ku, Yokohama, 226-8503, Japan. hiro@res.titech.ac.jp.
  • # Contributed equally.
PMID: 36463250 DOI: 10.1038/s41598-022-25079-4
Abstract

New matrix metalloproteinase 1 (MMP-1) inhibitors were predicted using the structure-activity relationship (SAR) transfer method based on a series of analogues of kinesin-like protein 11 (KIF11) inhibitors. Compounds 5-7 predicted to be highly potent against MMP-1 were synthesized and tested for MMP-1 inhibitory activity. Among these, compound 6 having a Cl substituent at the R1 site was found to possess CA. 3.5 times higher inhibitory activity against MMP-1 than the previously reported compound 4. The observed potency was consistent with the presence of an SAR transfer event between analogous MMP-1 and KIF11 inhibitors. Pharmacophore fitting revealed that the higher inhibitory activity of compound 6 compared to compound 4 against MMP-1 might be due to a halogen bond interaction between the Cl substituent of compound 6 and residue ARG214 of MMP-1.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-152092
    99.10%, MMP-1 Inhibitor
    MMP