Robust design of some selective matrix metalloproteinase-2 inhibitors over matrix metalloproteinase-9 through in silico/fragment-based lead identification and de novo lead modification: Syntheses and biological assays |
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| Institution: | 1. Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, PO Box 17020, Jadavpur University, Kolkata 700032, India;2. Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata 700032, India;3. Department of Chemical Technology, University of Calcutta, 92, APC Ray Road, Kolkata 700009, India;1. Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar 788011, Assam, India;2. Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza, Egypt;2. Department of Pharmacology and Biochemistry, Faculty of Pharmaceutical Sciences & Pharmaceutical Industries, Future University in Egypt, 12311 Cairo, Egypt;3. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, The British University in Egypt, El-Sherouk, Cairo, Egypt;1. Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, D-48149 Münster, Germany;2. Klinik für Nuklearmedizin, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, D-48149 Münster, Germany;3. European Institute for Molecular Imaging, Westfälische Wilhelms-Universität Münster, Waldeyerstraße 15, D-48149 Münster, Germany;4. Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), University of Münster, Waldeyerstraße 15, D-48149 Münster, Germany;1. Laboratory of Drug Design and Discovery, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University, Sagar 470003, Madhya Pradesh, India;2. Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, PO Box 17020, Jadavpur University, Kolkata 700032, West Bengal, India;1. Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India;2. Department of Chemical Technology, University of Calcutta, 92, APC Ray Road, Kolkata 700009, India;1. Dipartimento di Chimica e Chimica Industriale, Via Giuseppe Moruzzi, 13, 56124 Pisa, Italy;2. Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saul?tekio 7, Vilnius LT-10257, Lithuania;3. Department of Bioinformatics, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saul?tekio 7, Vilnius LT-10257, Lithuania |
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| Abstract: | Broad range of selectivity possesses serious limitation for the development of matrix metalloproteinase-2 (MMP-2) inhibitors for clinical purposes. To develop potent and selective MMP-2 inhibitors, initially multiple molecular modeling techniques were adopted for robust design. Predictive and validated regression models (2D and 3D QSAR and ligand-based pharmacophore mapping studies) were utilized for estimating the potency whereas classification models (Bayesian and recursive partitioning analyses) were used for determining the selectivity of MMP-2 inhibitors over MMP-9. Bayesian model fingerprints were used to design selective lead molecule which was modified using structure-based de novo technique. A series of designed molecules were prepared and screened initially for inhibitions of MMP-2 and MMP-9, respectively, as these are designed followed by other MMPs to observe the broader selectivity. The best active MMP-2 inhibitor had IC50 value of 24 nM whereas the best selective inhibitor (IC50 = 51 nM) showed at least 4 times selectivity to MMP-2 against all tested MMPs. Active derivatives were non-cytotoxic against human lung carcinoma cell line—A549. At non-cytotoxic concentrations, these inhibitors reduced intracellular MMP-2 expression up to 78% and also exhibited satisfactory anti-migration and anti-invasive properties against A549 cells. Some of these active compounds may be used as adjuvant therapeutic agents in lung cancer after detailed study. |
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| Keywords: | Matrix metalloproteinase 2 QSAR Pharmacophore mapping A549 cell line Invasion assay |
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