Dataset Information

Indole Inhibitors of MMP-13 for Arthritic Disorders.

ABSTRACT: Here, we described the design, by fragment merging and multiparameter optimization, of selective MMP-13 inhibitors that display an appropriate balance of potency and physicochemical properties to qualify as tool compounds suitable for in vivo testing. Optimization of potency was guided by structure-based insights, specifically to replace an ester moiety and introduce polar directional hydrogen bonding interactions in the core of the molecule. By introducing polar enthalpic interactions in this series of inhibitors, the overall beneficial physicochemical properties were maintained. These physicochemical properties translated to excellent drug-like properties beyond potency. In a murine model of rheumatoid arthritis, treatment of mice with selective inhibitors of MMP-13 resulted in a statistically significant reduction in the mean arthritic score vs control when dosed over a 14 day period.

SUBMITTER: Taylor SJ

PROVIDER: S-EPMC8319936 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Indole Inhibitors of MMP-13 for Arthritic Disorders.

Taylor Steven J SJ Abeywardane Asitha A Liang Shuang S Xiong Zhaoming Z Proudfoot John R JR Farmer Bennett Sandy BS Gao Donghong A DA Heim-Riether Alexander A Smith-Keenan Lana Louise LL Muegge Ingo I Yu Yang Y Zhang Qiang Q Souza Donald D Panzenbeck Mark M Goldberg Daniel D Hill-Drzewi Melissa M Margarit Mariana M Collins Brandon B Li John Xiang JX Zuvela-Jelaska Ljiljana L Li Jun J Farrow Neil A NA

ACS omega 20210719 29

Here, we described the design, by fragment merging and multiparameter optimization, of selective MMP-13 inhibitors that display an appropriate balance of potency and physicochemical properties to qualify as tool compounds suitable for <i>in vivo</i> testing. Optimization of potency was guided by structure-based insights, specifically to replace an ester moiety and introduce polar directional hydrogen bonding interactions in the core of the molecule. By introducing polar enthalpic interactions in ...[more]

PMID: 34337203

Similar Datasets

Project description:BackgroundMMP-13, a zinc dependent protease which catalyses the cleavage of type II collagen, is expressed in osteoarthritis (OA) and rheumatoid arthritis (RA) patients, but not in normal adult tissues. Therefore, the protease has been intensively studied as a target for the inhibition of progression of OA and RA. Recent reports suggest that selective inhibition of MMP-13 may be achieved by targeting the hemopexin (Hpx) domain of the protease, which is critical for substrate specificity. In this study, we applied a cheminformatics-based drug design approach for the identification and characterization of inhibitors targeting the amino acid residues characteristic to Hpx domain of MMP-13; these inhibitors may potentially be employed in the treatment of OA and RA.Methodology/principal findingsSequence-based mutual information analysis revealed five characteristic (completely conserved and unique), putative functional residues of the Hpx domain of MMP-13 (these residues hereafter are referred to as HCR-13(pf)). Binding of a ligand to as many of the HCR-13(pf) is postulated to result in an increased selective inhibition of the Hpx domain of MMP-13. Through the in silico structure-based high-throughput virtual screening (HTVS) method of Glide, against a large public library of 16908 molecules from Maybridge, PubChem and Binding, we identified 25 ligands that interact with at least one of the HCR-13(pf). Assessment of cross-reactivity of the 25 ligands with MMP-1 and MMP-8, members of the collagenase family as MMP-13, returned seven lead molecules that did not bind to any one of the putative functional residues of Hpx domain of MMP-1 and any of the catalytic active site residues of MMP-1 and -8, suggesting that the ligands are not likely to interact with the functional or catalytic residues of other MMPs. Further, in silico analysis of physicochemical and pharmacokinetic parameters based on Lipinski's rule of five and ADMET (absorption, distribution, metabolism, excretion and toxicity) respectively, suggested potential utility of the compounds as drug leads.Conclusions/significanceWe have identified seven distinct drug-like molecules binding to the HCR-13(pf) of MMP-13 with no observable cross-reactivity to MMP-1 and MMP-8. These molecules are potential selective inhibitors of MMP-13 that can be experimentally validated and their backbone structural scaffold could serve as building blocks in designing drug-like molecules for OA, RA and other inflammatory disorders. The systematic cheminformatics-based drug design approach applied herein can be used for rational search of other public/commercial combinatorial libraries for more potent molecules, capable of selectively inhibiting the collagenolytic activity of MMP-13.

Dataset Information

Indole Inhibitors of MMP-13 for Arthritic Disorders.

Publications

Indole Inhibitors of MMP-13 for Arthritic Disorders.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets