caa a22 4500 445879157 CHVBK 20180317145537.0 cr unu---uuuuu 170323e20110501xx s 000 0 eng 10.1007/s11030-010-9262-5 doi (NATIONALLICENCE)springer-10.1007/s11030-010-9262-5 Natural products as DNA methyltransferase inhibitors: a computer-aided discovery approach [Elektronische Daten] [Jose Medina-Franco, Fabian López-Vallejo, Dirk Kuck, Frank Lyko] DNA methyltransferases (DNMTs) represent promising targets for the development of unique anticancer drugs. However, all DNMT inhibitors currently in clinical use are nonselective cytosine analogs with significant cytotoxic side-effects. Several natural products, covering diverse chemical classes, have indicated DNMT inhibitory activity, but these effects have yet to be systematically evaluated. In this study, we provide experimental data suggesting that two of the most prominent natural products associated with DNA methylation inhibition, (−)-epigallocathechin-3-gallate (EGCG) and curcumin, have little or no pharmacologically relevant inhibitory activity. We therefore conducted a virtual screen of a large database of natural products with a validated homology model of the catalytic domain of DNMT1. The virtual screening focused on a lead-like subset of the natural products docked with DNMT1, using three docking programs, following a multistep docking approach. Prior to docking, the lead-like subset was characterized in terms of chemical space coverage and scaffold content. Consensus hits with high predicted docking affinity for DNMT1 by all three docking programs were identified. One hit showed DNMT1 inhibitory activity in a previous study. The virtual screening hits were located within the biological-relevant chemical space of drugs, and represent potential unique DNMT inhibitors of natural origin. Validation of these virtual screening hits is warranted. Springer Science+Business Media B.V., 2010 Cancer nationallicence Curcumin nationallicence DNA methylation nationallicence Drug discovery nationallicence EGCG nationallicence Natural product database nationallicence Virtual screening nationallicence DNMT : DNA methyltransferase nationallicence EGCG : (−)-epigallocathechin-3-gallate nationallicence HBA : Hydrogen bond acceptor nationallicence HBD : Hydrogen bond donor nationallicence MOE : Molecular operating environment nationallicence MW : Molecular weight nationallicence NCI : National Cancer Institute nationallicence RB : Rotatable bond nationallicence SAH : S-adenosyl-l-homocysteine nationallicence SAM : S-adenosyl-l-methionine nationallicence SP : Standard precision nationallicence TPSA : Topological polar surface area nationallicence XP : Extra precision nationallicence Medina-Franco Jose Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, 34987, Port St. Lucie, FL, USA aut López-Vallejo Fabian Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, 34987, Port St. Lucie, FL, USA aut Kuck Dirk Division of Epigenetics, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 580, 69120, Heidelberg, Germany aut Lyko Frank Division of Epigenetics, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 580, 69120, Heidelberg, Germany aut Molecular Diversity Springer Netherlands 15/2(2011-05-01), 293-304 1381-1991 15:2<293 2011 15 11030 https://doi.org/10.1007/s11030-010-9262-5 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11030-010-9262-5 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Medina-Franco Jose Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, 34987, Port St. Lucie, FL, USA aut NATIONALLICENCE 700 1- López-Vallejo Fabian Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, 34987, Port St. Lucie, FL, USA aut NATIONALLICENCE 700 1- Kuck Dirk Division of Epigenetics, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 580, 69120, Heidelberg, Germany aut NATIONALLICENCE 700 1- Lyko Frank Division of Epigenetics, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 580, 69120, Heidelberg, Germany aut NATIONALLICENCE 773 0- Molecular Diversity Springer Netherlands 15/2(2011-05-01), 293-304 1381-1991 15:2<293 2011 15 11030 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer