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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• 作者：Nilanjan Adhikari^a ; ^&dagger ; ; Amit K. Halder^a ; ^&dagger ; ; Sumana Mallick^b ; Achintya Saha^c ; Kishna D. Saha^b ; Tarun Jha^a ; ^{tjupharm@yahoo.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：CoMFA ; comparative molecular field analysis ; CoMSIA ; comparative molecular similarity analysis ; DS ; discovery studio software ; FT-IR ; Fourier transform infrared spectroscopy ; HDAC ; histone deacetylase ; HMBC ; heteronuclear multiple bond correlation ; MMP ; matrix metalloproteinase ; MM-GBSA ; molecular mechanics combined with generalized Born and surface-area salvation ; Mp ; melting point ; MS ; mass spectroscopy ; MLR ; multiple linear regression ; NMR ; nuclear magnetic resonance ; QPLD ; quantum polarized
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 September 2016
• 年：2016
• 卷：24
• 期：18
• 页码：4291-4309
• 全文大小：3359 K

文摘

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.