%0 Journal Article %1 Kruger2012Global %A Kruger, Felix A. %A Overington, John P. %D 2012 %I Public Library of Science %J PLOS Computational Biology %K protein-ligand-interactions %N 1 %P e1002333+ %R 10.1371/journal.pcbi.1002333 %T Global Analysis of Small Molecule Binding to Related Protein Targets %U http://dx.doi.org/10.1371/journal.pcbi.1002333 %V 8 %X We report on the integration of pharmacological data and homology information for a large scale analysis of small molecule binding to related targets. Differences in small molecule binding have been assessed for curated pairs of human to rat orthologs and also for recently diverged human paralogs. Our analysis shows that in general, small molecule binding is conserved for pairs of human to rat orthologs. Using statistical tests, we identified a small number of cases where small molecule binding is different between human and rat, some of which had previously been reported in the literature. Knowledge of species specific pharmacology can be advantageous for drug discovery, where rats are frequently used as a model system. For human paralogs, we demonstrate a global correlation between sequence identity and the binding of small molecules with equivalent affinity. Our findings provide an initial general model relating small molecule binding and sequence divergence, containing the foundations for a general model to anticipate and predict within-target-family selectivity. Many drugs are small molecules that specifically bind to proteins involved in disease related processes. In this way, drugs modulate the function of a targeted protein and ultimately the process causing the disease. The development of drugs crucially relies on assays that measure the potency of the effect a small molecule exerts on its protein target. We compared the potencies of small molecules measured for human proteins and the corresponding (orthologous) protein in rat. Our results suggest that, after subtraction of statistical noise, most human proteins are equally susceptible to small molecule binding as their orthologs in rats. However, we identified a small number of exceptions to this rule, for example the histamine H3 receptor, a protein of the central nervous system. We also compared the potency of small molecules measured against a human protein and another member of the same protein family. In drug development it is often desired to target a protein selectively over other related proteins. The observed differences were generally greater than the statistical noise, indicating that most of the small molecules in our study have some degree of selectivity within protein families.

@article{Kruger2012Global, abstract = {We report on the integration of pharmacological data and homology information for a large scale analysis of small molecule binding to related targets. Differences in small molecule binding have been assessed for curated pairs of human to rat orthologs and also for recently diverged human paralogs. Our analysis shows that in general, small molecule binding is conserved for pairs of human to rat orthologs. Using statistical tests, we identified a small number of cases where small molecule binding is different between human and rat, some of which had previously been reported in the literature. Knowledge of species specific pharmacology can be advantageous for drug discovery, where rats are frequently used as a model system. For human paralogs, we demonstrate a global correlation between sequence identity and the binding of small molecules with equivalent affinity. Our findings provide an initial general model relating small molecule binding and sequence divergence, containing the foundations for a general model to anticipate and predict within-target-family selectivity. Many drugs are small molecules that specifically bind to proteins involved in disease related processes. In this way, drugs modulate the function of a targeted protein and ultimately the process causing the disease. The development of drugs crucially relies on assays that measure the potency of the effect a small molecule exerts on its protein target. We compared the potencies of small molecules measured for human proteins and the corresponding (orthologous) protein in rat. Our results suggest that, after subtraction of statistical noise, most human proteins are equally susceptible to small molecule binding as their orthologs in rats. However, we identified a small number of exceptions to this rule, for example the histamine H3 receptor, a protein of the central nervous system. We also compared the potency of small molecules measured against a human protein and another member of the same protein family. In drug development it is often desired to target a protein selectively over other related proteins. The observed differences were generally greater than the statistical noise, indicating that most of the small molecules in our study have some degree of selectivity within protein families.}, added-at = {2018-12-02T16:09:07.000+0100}, author = {Kruger, Felix A. and Overington, John P.}, biburl = {https://www.bibsonomy.org/bibtex/206377748959a6497623ca963d335bdd6/karthikraman}, citeulike-article-id = {10228105}, citeulike-linkout-0 = {http://dx.doi.org/10.1371/journal.pcbi.1002333}, citeulike-linkout-1 = {http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257267/}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/22253582}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=22253582}, day = 12, doi = {10.1371/journal.pcbi.1002333}, interhash = {7e0dd56c3a8715e154fe6ac3125b3edb}, intrahash = {06377748959a6497623ca963d335bdd6}, issn = {1553-7358}, journal = {PLOS Computational Biology}, keywords = {protein-ligand-interactions}, month = jan, number = 1, pages = {e1002333+}, pmcid = {PMC3257267}, pmid = {22253582}, posted-at = {2012-02-01 07:52:45}, priority = {2}, publisher = {Public Library of Science}, timestamp = {2018-12-02T16:09:07.000+0100}, title = {Global Analysis of Small Molecule Binding to Related Protein Targets}, url = {http://dx.doi.org/10.1371/journal.pcbi.1002333}, volume = 8, year = 2012 }