Applications of 3D-QSAR and structure-based pharmacophore modeling, virtual screening, ADMET, and molecular docking of p
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Med Chem Res (2013) 22:4818–4829 DOI 10.1007/s00044-013-0492-9
ORIGINAL RESEARCH
Applications of 3D-QSAR and structure-based pharmacophore modeling, virtual screening, ADMET, and molecular docking of putative MAPKAP-K2 (MK2) inhibitors Tai-Jin Wang • Lu Zhou • Jia Fei Zi-Cheng Li • Lu-fen He
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Received: 11 October 2012 / Accepted: 11 January 2013 / Published online: 26 January 2013 Ó Springer Science+Business Media New York 2013
Abstract MAPKAP-K2 (MK2) belongs to the Ser/Thr kinase family, and has emerged as a highly favored target in the search for efficacious and safe anti-inflammatory drug. Thus, 3D-QSAR and structure-based pharmacophore models were developed in this study to identify new potential leads inhibiting MK2 as an efficient way to treat rheumatoid arthritis. Furthermore, these two kinds of models were cascaded together to reduce false positives in virtual screening. The selected compounds were further analyzed and refined using drug-like filters and ADMET analysis. Subsequently, 105 recruited hits were docked into MK2-binding site with GOLD. Finally, 12 molecules were selected as potential MK2 inhibitors, and their consensus score and their structural diversity were evaluated. Keywords MK2 Anti-inflammatory drug 3D-QSAR Virtual screening Molecular docking
Introduction Mitogen-activated protein kinases (MAPKs) belong to the Ser/Thr kinase family which comprises three subfamilies: the p42/p44 extracellular regulated kinases (ERKs), the c-Jun N-terminal kinases (JNKs), and the p38 MAPKs (Hammaker and Firestein, 2009). Downstream of MAPKs,
Electronic supplementary material The online version of this article (doi:10.1007/s00044-013-0492-9) contains supplementary material, which is available to authorized users. T.-J. Wang L. Zhou (&) J. Fei Z.-C. Li L. He College of Chemical Engineering, Sichuan University, Chengdu 610065, Sichuan, China e-mail: [email protected]; [email protected]
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there are three structurally related MAPK-activated protein kinases (MK2, MK3, and MK5) (Gaestel, 2006). P38, which has four homologous isoforms—a, b, c, and d— plays a key role in rheumatoid arthritis (RA). It can regulate cytokine expression and be activated in the rheumatoid synovium. Furthermore, inhibition of p38 suppresses numerous cytokines implicated in RA and decreases fever and cytokine production in a human LPS challenge model. Thus, P38, especially p38a, appears to be an attractive target. And a number of compounds that inhibit the p38a MAPKs have entered clinical trials for the treatment of RA and psoriasis, but side effects have prevented their progression to phase III clinical trials (Cohen, 2009). The cause of failures of p38 in the clinic is considered unknown (Hammaker and Firestein, 2009). Owing to these problems with the use of inhibitors of p38a, targets downstream to p38 MAPKs, such as MK2 and MK3, become more attractive for anti-inflammatory drugs. In contrast to P38a, MK2 and MK3, do not participate in the feedback signaling loop to TAK1 (Ronkina et al., 2010). Therefore, MK2
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