title: A preliminary in silico lead series of 2-phthalimidinoglutaric acid analogues designed as MMP-3 inhibitors.
abstract: Matrix metalloproteinases (MMPs) have been the subject of intense research because of their roles in tumor metastasis and in the rise and spread of degenerative diseases such as osteo- and rheumatoid arthritis. A preliminary class of 140 druglike, small-molecule matrix metalloproteinase-3 inhibitors, intended as starting scaffolds for optimization and synthesis, has been designed in silico using a series of highly predictive three-dimensional quantitative structure-activity relationship models, including comparative molecular field analysis and comparative molecular similarity indices analysis, with docking and scoring. Thalidomide was chosen as the skeleton on which to base the new lead series, as it moderately inhibits MMP-3, is antiangiogenic, and lends itself easily to structural modifications. Most of the new compounds demonstrate medium to high predicted biological activity and good bioavailability as estimated by the octanol-water partition coefficient ClogP. Compound 102 in particular exhibits extremely favorable predicted activity against MMP-3; is moderately bioavailable; satisfies Lipinski's Rule of Five; and shows promise for further optimization, synthesis, and experimental evaluation as a potential adjunct anticancer or antirheumatic therapeutic.
authors.affiliation: Department of Chemistry and Minnesota Supercomputing Institute, University of Minnesota, 207 Pleasant St SE, Minneapolis, Minnesota 55455, USA. amni@chem.umn.edu
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Amin
authors.forename: William J
authors.initials: WJ
authors.lastname: Welsh
mesh_terms: D001665:Binding Sites; D005977:Glutarates / Q000737:chemistry / Q000494:pharmacology*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D013792:Thalidomide / Q000378:metabolism
chemical_list: D005977:Glutarates; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D013792:Thalidomide; D019278:Matrix Metalloproteinase 3; C035736:glutaric acid