title: In vitro biological evaluation of glyburide as potential inhibitor of collagenases.
abstract: In tissues with upregulated MMP activity, MMP inhibition remains one of the key strategies. Potential inhibitors of MMPs have been tested for almost 30 years, but none have reached clinical utility due to bioavailability issues and adverse effects. This study utilized the approach of drug repurposing for exploring glyburide as a potential inhibitor against collagenases. In silico molecular docking studies were carried out to probe the interactions of glyburide with the active site Zn. Collagenase enzyme activity measurements and zymography analyses using conditioned medium from lung fibroblasts, rheumatoid synovial fibroblasts, and osteoblasts were carried out to confirm the inhibitory activity. Glyburide binds and interacts with the catalytic Zn residues of the collagenases, as evidenced by in silico molecular docking studies. Fluorescence enzyme activity measurements reveal that glyburide inhibits peptide substrate cleavage by all three collagenases in a dose-dependent manner. Collagen zymography studies validated inhibition of these collagenases by glyburide. These results identify glyburide as a potential inhibitor of collagenases and provide an insight into the mechanism of action of this small molecule. Thus, glyburide may offer additional advantages in diabetics, in controlling MMP activation and collagen degradation and could aid in the treatment of diseases with aberrant MMP activity.
authors.affiliation: Department of Molecular Biology, Institute of Genetics & Hospital for Genetic Diseases, Osmania University, Begumpet, Hyderabad, India.
authors.forename: Vijaya Lakshmi
authors.initials: VL
authors.lastname: Bodiga
authors.affiliation: Department of Biotechnology, KL University, Green Fields, Vaddeswaram, Andhra Pradesh, India.
authors.forename: Sasidhar Reddy
authors.initials: SR
authors.lastname: Eda
authors.affiliation: Department of Biotechnology, KL University, Green Fields, Vaddeswaram, Andhra Pradesh, India.
authors.forename: Saishashank
authors.initials: S
authors.lastname: Chavali
authors.affiliation: Department of Biotechnology, KL University, Green Fields, Vaddeswaram, Andhra Pradesh, India.
authors.forename: Nagasaisreelekha Nagavalli
authors.initials: NN
authors.lastname: Revur
authors.affiliation: Department of Medicine, Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry, Kakatiya University, Vidyaranyapuri, Warangal 506009, Andhra Pradesh, India.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Thokala
authors.affiliation: Department of Biochemistry, Kakatiya University, Vidyaranyapuri, Warangal 506009, Andhra Pradesh, India. Electronic address: sbodiga@gmail.com.
authors.forename: Sreedhar
authors.initials: S
authors.lastname: Bodiga
mesh_terms: D017364:Collagenases / Q000737:chemistry / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects; D005905:Glyburide / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D020782:Matrix Metalloproteinases / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D017364:Collagenases; D020782:Matrix Metalloproteinases; D005905:Glyburide
keywords: Collagenases; Glyburide; Zymography