Designing new generation of potent inhibitors against membrane-type matrix metalloproteinase-2: a computational effort against multiple myeloma. Issue 13 (1st September 2020)

• Record Type: Journal Article
• Authors: Fakhari, Shohreh; Stefanucci, Azzurra; Mollica, Adriano; Nikkhoo, Bahram; Tafsiri, Elham; Jalili, Ali; Mirzaie, Sako
• Is Part Of: Journal of biomolecular structure & dynamics. Volume 38:Issue 13(2020)
• Page Start: 3879
• Page End: 3891
• Publication Date: 2020-09-01
• Subjects: Matrix metalloproteinases -- MT2-MMP -- MT-LOOP -- multiple myeloma -- molecular dynamics; Biomolecules -- Periodicals; Molecular structure -- Periodicals; Molecular Biology -- Periodicals; Biomechanics -- Periodicals; 572
• DOI: 10.1080/07391102.2019.1670736
• Languages: English
• ISSNs: 0739-1102

Abstract

Abstract: Matrix metalloproteinases (MMPs) play important roles in cancer progression and, despite their inhibitors have failed in the clinical trials, they have always been considered as suitable targets for the treatment of tumor. We have recently shown that membrane type (MT) 2-MMPs, is selectively expressed in multiple myeloma (MM) cells and mediates the metastatic characteristics of these cells. In this study, we designed efficient inhibitors against MT2-MMP using state-of-art molecular modeling methods. First, the 3D structure of MT2-MMP was predicted. Then, the proposed potent inhibitors against two regions of the catalytic domain of MT2-MMP (active site and MT-LOOP) were identified through molecular docking, QM-MM and molecular dynamics simulations from a set of compounds in Analyticon library, IBS library, Maybridge screening fragment library and drugbank library. Moreover, ADME estimation showed that pharmacokinetic properties of inhibitors are in the acceptable range for humans. Finally, our data suggested that compounds 'structures.722' (dobutamine) and 'M2' are suitable candidates to inhibit MT2-MMP for further examination in the laboratory. Communicated by Ramaswamy H. Sarma