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

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

Yasunobu Asawa  1   2 , Atsushi Yoshimori  3 , Jürgen Bajorath #  4 , Hiroyuki Nakamura #  5
Affiliations

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

Yasunobu Asawa et al. Sci Rep. .

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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Activity cliff prediction using the SAR matrix (SARM) method. (a) Schematic summary of SARM modeling. (b) Prediction of an activity cliff formed by MMP-1 inhibitors. (c) Structure of designed control compounds.
Figure 2
Figure 2
(a) Pharmacophore fitting of compound 4 to the SC44463 pharmacophore model; (b) Binding interaction of compound 4 with MMP-1.
Scheme 1
Scheme 1
Synthesis of compounds 3–6. Conditions: (a) LDA, MeI, THF, − 78 °C; (b) LDA, allyl bromide, THF, − 78 °C; (c) O3, CH2Cl2, PPh3 − 78 °C to r.t.; (d) D-alanine methyl ester, Zn, acetic acid, reflux (15: 29%; 16: 47%; 17: 49%; 18: 29% yield for 4 steps; d.r. = 1:1); (e) NH2OH, MeOH (3: 72%; 3′: 98%; 4: 90%; 4′: 72%; 5: 49%; 6: 43% yield).
See this image and copyright information in PMC

References

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