title: Doing the methylene shuffle--further insights into the inhibition of mitotic kinesin Eg5 with S-trityl L-cysteine.
abstract: S-Trityl L-cysteine (STLC) is an inhibitor of the mitotic kinesin Eg5 with potential as an antimitotic chemotherapeutic agent. We previously reported the crystal structure of the ligand-protein complex, and now for the first time, have quantified the interactions using a molecular dynamics based approach. Based on these data, we have explored the SAR of the trityl head group using the methylene shuffle strategy to expand the occupation of one of the hydrophobic pockets. The most potent compounds exhibit strong (<100 nM) inhibition of Eg5 in the basal ATPase assay and inhibit growth in a variety of tumour-derived cell lines.
authors: Strathclyde Institute of Pharmacy and Biomedical Sciences, 161 Cathedral Street, University of Strathclyde, Glasgow G4 0RE, Scotland, UK.
authors: Murad N
authors: MN
authors: Abualhasan
authors: James A D
authors: JA
authors: Good
authors: Kitiyaporn
authors: K
authors: Wittayanarakul
authors: Nahoum G
authors: NG
authors: Anthony
authors: Giacomo
authors: G
authors: Berretta
authors: Oliver
authors: O
authors: Rath
authors: Frank
authors: F
authors: Kozielski
authors: Oliver B
authors: OB
authors: Sutcliffe
authors: Simon P
authors: SP
authors: Mackay
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003545:Cysteine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C470243:KIF11 protein, human; C003724:3-tritylthio-L-alanine; D016547:Kinesins; D003545:Cysteine