Prediction of an MMP-1 inhibitor activity cliff using the SAR matrix approach and its experimental validation

Yasunobu Asawa; Atsushi Yoshimori; Jürgen Bajorath; Hiroyuki Nakamura

doi:10.1038/s41598-020-71696-2

Prediction of an MMP-1 inhibitor activity cliff using the SAR matrix approach and its experimental validation

Sci Rep. 2020 Sep 7;10(1):14710. doi: 10.1038/s41598-020-71696-2.

Authors

Yasunobu Asawa^{1

2}, Atsushi Yoshimori³, Jürgen Bajorath^#⁴, Hiroyuki Nakamura^#⁵

Affiliations

¹ Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, Nagatsuta-cho, Midori-ku, Yokohama, 226-8503, Japan.
² School of Life Science and Technology, Tokyo Institute of Technology, Nagatsuta-cho, Midori-ku, Yokohama, 226-8503, Japan.
³ Institute for Theoretical Medicine, Inc., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-0012, Japan.
⁴ Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Endenicher Allee 19c, 53115, Bonn, Germany. bajorath@bit.uni-bonn.de.
⁵ Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, Nagatsuta-cho, Midori-ku, Yokohama, 226-8503, Japan. hiro@res.titech.ac.jp.

^# Contributed equally.

Abstract

A matrix metalloproteinase 1 (MMP-1) inhibitor activity cliff was predicted using the SAR Matrix method. Compound 4 was predicted as a highly potent activity cliff partner and found to possess 60 times higher inhibitory activity against MMP-1 than the structurally related compound 3. Furthermore, pharmacophore fitting of synthesized compounds indicated that the correctly predicted activity cliff was caused by interactions between the trifluoromethyl group at para position in compound 4 and residue ARG214 of MMP-1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Matrix Metalloproteinase 1 / metabolism*
Matrix Metalloproteinase Inhibitors / chemistry*
Molecular Docking Simulation
Quantitative Structure-Activity Relationship

Substances

Matrix Metalloproteinase Inhibitors
Matrix Metalloproteinase 1