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Identification of potential small molecule binding pockets on Rho family GTPases Ortiz Sánchez, Juan Manuel Nichols, SE Sayyah, J Brown, JH McCammon, JA et al. Agència de Gestió d'Ajuts Universitaris i de Recerca Kinesin Rho guanine nucleotide binding protein Rho GTPases are conformational switches that control a wide variety of signaling pathways critical for eukaryotic cell development and proliferation. They represent attractive targets for drug design as their aberrant function and deregulated activity is associated with many human diseases including cancer. Extensive high-resolution structures (.100) and recent mutagenesis studies have laid the foundation for the design of new structure-based chemotherapeutic strategies. Although the inhibition of Rho signaling with drug-like compounds is an active area of current research, very little attention has been devoted to directly inhibiting Rho by targeting potential allosteric non-nucleotide binding sites. By avoiding the nucleotide binding site, compounds may minimize the potential for undesirable off-target interactions with other ubiquitous GTP and ATP binding proteins. Here we describe the application of molecular dynamics simulations, principal component analysis, sequence conservation analysis, and ensemble small-molecule fragment mapping to provide an extensive mapping of potential small-molecule binding pockets on Rho family members. Characterized sites include novel pockets in the vicinity of the conformationaly responsive switch regions as well as distal sites that appear to be related to the conformations of the nucleotide binding region. Furthermore the use of accelerated molecular dynamics simulation, an advanced sampling method that extends the accessible time-scale of conventional simulations, is found to enhance the characterization of novel binding sites when conformational changes are important for the protein mechanism. 2012-07-16 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Ortiz-Sanchez JM, Nichols SE, Sayyah J, Brown JH, McCammon JA, et al. (2012) Identification of Potential Small Molecule Binding Pockets on Rho Family. PLoS ONE 7(7): e40809. doi:10.1371/journal.pone.0040809 http://hdl.handle.net/2072/212451 eng Els ajuts de l'AGAUR;2009BP_A 00126 info:eu-repo/semantics/openAccess 13 p. application/pdf Jens Kleinjung, MRC National Institute for Medical Research, United Kingdom RECERCAT (Dipòsit de la Recerca de Catalunya)