Ligand configurational entropy and protein binding Export

@article{citeulike:1557938, abstract = {The restriction of a small molecule's motion on binding to a protein causes a loss of configurational entropy, and thus a penalty in binding affinity. Some energy models used in computer-aided ligand design neglect this entropic penalty, whereas others account for it based on an expected drop in the number of accessible rotamers upon binding. However, the validity of the physical assumptions underlying the various approaches is largely unexamined. The present study addresses this issue by using Mining Minima calculations to analyze the association of amprenavir with HIV protease. The computed loss in ligand configurational entropy is large, contributing [\~{}]25 kcal/mol (4.184 kJ/kcal) to {Delta}G{degrees}. Most of this loss results from narrower energy wells in the bound state, rather than a drop in the number of accessible rotamers. Coupling among rotation/translation and internal degrees of freedom complicates the decomposition of the entropy change into additive terms. The results highlight the potential to gain affinity by designing conformationally restricted ligands and have implications for the formulation of energy models for ligand scoring. 10.1073/pnas.0610494104}, author = {Chang, Chia-En A. and Chen, Wei and Gilson, Michael K.}, citeulike-article-id = {1557938}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0610494104}, citeulike-linkout-1 = {http://www.pnas.org/content/104/5/1534.full.abstract}, citeulike-linkout-2 = {http://www.pnas.org/content/104/5/1534.full.full.pdf}, citeulike-linkout-3 = {http://www.pnas.org/cgi/content/abstract/104/5/1534}, citeulike-linkout-4 = {http://view.ncbi.nlm.nih.gov/pubmed/17242351}, citeulike-linkout-5 = {http://www.hubmed.org/display.cgi?uids=17242351}, day = {30}, doi = {10.1073/pnas.0610494104}, journal = {PNAS}, keywords = {amprenavir}, month = {January}, number = {5}, pages = {1534--1539}, posted-at = {2009-01-27 21:38:12}, priority = {2}, title = {Ligand configurational entropy and protein binding}, url = {http://dx.doi.org/10.1073/pnas.0610494104}, volume = {104}, year = {2007} }

TY - JOUR ID - citeulike:1557938 L3 - citeulike-article-id:1557938 N2 - The restriction of a small molecule's motion on binding to a protein causes a loss of configurational entropy, and thus a penalty in binding affinity. Some energy models used in computer-aided ligand design neglect this entropic penalty, whereas others account for it based on an expected drop in the number of accessible rotamers upon binding. However, the validity of the physical assumptions underlying the various approaches is largely unexamined. The present study addresses this issue by using Mining Minima calculations to analyze the association of amprenavir with HIV protease. The computed loss in ligand configurational entropy is large, contributing [~]25 kcal/mol (4.184 kJ/kcal) to {Delta}G{degrees}. Most of this loss results from narrower energy wells in the bound state, rather than a drop in the number of accessible rotamers. Coupling among rotation/translation and internal degrees of freedom complicates the decomposition of the entropy change into additive terms. The results highlight the potential to gain affinity by designing conformationally restricted ligands and have implications for the formulation of energy models for ligand scoring. 10.1073/pnas.0610494104 IS - 5 JF - PNAS EP - 1539 TI - Ligand configurational entropy and protein binding VL - 104 SP - 1534 KW - amprenavir AU - Chang, Chia-En AU - Chen, Wei AU - Gilson, Michael PY - 2007/01/30/ UR - http://dx.doi.org/10.1073/pnas.0610494104 ER -