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Design and Discovery of Plasmepsin II Inhibitors Using an Automated Workflow on Large-Scale Grids
Degliesposti, Gianluca,Kasam, Vinod,Da Costa, Ana,Kang, Hee-Kyoung,Kim, Nahyun,Kim, Do-Won,Breton, Vincent,Kim, Doman,Rastelli, Giulio Wiley (John WileySons) 2009 ChemMedChem Vol.4 No.7
<P>Novel and potent inhibitors of Plasmodium falciparum plasmepsin II were identified by post-processing the results of a docking screening with BEAR, a recently reported procedure for the refinement and rescoring of docked ligands in virtual screening. FRET substrate degradation assays performed on the 30 most promising compounds resulted in 26 inhibitors with IC(50) values ranging from 4.3 nM to 1.8 microM.Herein we report the discovery of novel and potent inhibitors of Plasmodium falciparum plasmepsin II using GRID computing infrastructures. These compounds were identified by post-processing the results of a large docking screen of commercially available compounds using an automated procedure based on molecular dynamics refinement and binding free-energy estimation using MM-PBSA and MM-GBSA. Among the best-scored compounds, four highly populated and promising chemical classes were identified: N-alkoxyamidines, guanidines, amides, and ureas and thioureas. Thirty hit compounds representative of each class were selected on the basis of their favourable binding free energies and molecular interactions with key active site residues. These were experimentally validated using an inhibition assay based on FRET substrate degradation. Remarkably, 26 of the 30 tested compounds proved to be active as plasmepsin II inhibitors, with IC(50) values ranging from 4.3 nM to 1.8 microM.</P>
Proteasome Inhibitors with Pyrazole Scaffolds from Structure-Based Virtual Screening
Miller, Zachary,Kim, Keun-Sik,Lee, Do-Min,Kasam, Vinod,Baek, Si Eun,Lee, Kwang Hyun,Zhang, Yan-Yan,Ao, Lin,Carmony, Kimberly,Lee, Na-Ra,Zhou, Shou,Zhao, Qingquan,Jang, Yujin,Jeong, Hyun-Young,Zhan, Ch American Chemical Society 2015 Journal of medicinal chemistry Vol.58 No.4
<P>We performed a virtual screen of ∼340 000 small molecules against the active site of proteasomes followed by in vitro assays and subsequent optimization, yielding a proteasome inhibitor with pyrazole scaffold. The pyrazole-scaffold compound displayed excellent metabolic stability and was highly effective in suppressing solid tumor growth in vivo. Furthermore, the effectiveness of this compound was not negatively impacted by resistance to bortezomib or carfilzomib.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jmcmar/2015/jmcmar.2015.58.issue-4/jm501344n/production/images/medium/jm-2014-01344n_0008.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/jm501344n'>ACS Electronic Supporting Info</A></P>