Structure-Based Identification of Small Molecule Binding Sites Using a Free Energy Model Export

@article{citeulike:967826, abstract = {PMID: 17125203 We separately have shown that the maximal druglike affinity of a given binding site on a protein can be calculated on the basis of the binding-site structure alone by using a desolvation-based free energy model along with the notion that druglike ligands fall into certain physiochemical property ranges. Here, we present an approach where we reformulate the calculated druggability affinity as an additive free energy to facilitate the searching of whole protein surfaces for druglike binding sites. The highest-scoring patches in many cases represent known ligand-binding sites for druggable targets, but not for difficult targets. This approach differs from other approaches in that it does not simply identify pockets with the greatest volume but instead identifies pockets that are likely to be amenable to druglike small-molecule binding. Combining the method with a functional residue prediction method called SCA (statistical coupling analysis) results in the prediction of potentially druggable allosteric binding sites on p38alpha kinase.}, address = {Research Technology Center, Pfizer Global Research \& Development, Cambridge, Massachusetts 02139, Tufts University, Medford, Massachusetts 02139, and Brandeis University, Waltham, Massachusetts 02454.}, author = {Coleman, Ryan G. and Salzberg, Anna C. and Cheng, Alan C.}, citeulike-article-id = {967826}, citeulike-linkout-0 = {http://dx.doi.org/10.1021/ci600229z}, citeulike-linkout-1 = {http://pubs.acs.org/doi/abs/10.1021/ci600229z}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/17125203}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=17125203}, day = {1}, doi = {10.1021/ci600229z}, issn = {1549-9596}, journal = {Journal of Chemical Information and Modeling}, keywords = {coevolution, druggability}, month = {November}, number = {6}, pages = {2631--2637}, posted-at = {2006-11-30 04:20:19}, priority = {4}, title = {Structure-Based Identification of Small Molecule Binding Sites Using a Free Energy Model}, url = {http://dx.doi.org/10.1021/ci600229z}, volume = {46}, year = {2006} }

TY - JOUR ID - citeulike:967826 L3 - citeulike-article-id:967826 N2 - PMID: 17125203 We separately have shown that the maximal druglike affinity of a given binding site on a protein can be calculated on the basis of the binding-site structure alone by using a desolvation-based free energy model along with the notion that druglike ligands fall into certain physiochemical property ranges. Here, we present an approach where we reformulate the calculated druggability affinity as an additive free energy to facilitate the searching of whole protein surfaces for druglike binding sites. The highest-scoring patches in many cases represent known ligand-binding sites for druggable targets, but not for difficult targets. This approach differs from other approaches in that it does not simply identify pockets with the greatest volume but instead identifies pockets that are likely to be amenable to druglike small-molecule binding. Combining the method with a functional residue prediction method called SCA (statistical coupling analysis) results in the prediction of potentially druggable allosteric binding sites on p38alpha kinase. IS - 6 JF - Journal of Chemical Information and Modeling SN - 1549-9596 AD - Research Technology Center, Pfizer Global Research & Development, Cambridge, Massachusetts 02139, Tufts University, Medford, Massachusetts 02139, and Brandeis University, Waltham, Massachusetts 02454. EP - 2637 TI - Structure-Based Identification of Small Molecule Binding Sites Using a Free Energy Model VL - 46 SP - 2631 KW - coevolution KW - druggability AU - Coleman, Ryan AU - Salzberg, Anna AU - Cheng, Alan PY - 2006/11/01/ UR - http://dx.doi.org/10.1021/ci600229z ER -