title: mCSM-lig: quantifying the effects of mutations on protein-small molecule affinity in genetic disease and emergence of drug resistance.
abstract: The ability to predict how a mutation affects ligand binding is an essential step in understanding, anticipating and improving the design of new treatments for drug resistance, and in understanding genetic diseases. Here we present mCSM-lig, a structure-guided computational approach for quantifying the effects of single-point missense mutations on affinities of small molecules for proteins. mCSM-lig uses graph-based signatures to represent the wild-type environment of mutations, and small-molecule chemical features and changes in protein stability as evidence to train a predictive model using a representative set of protein-ligand complexes from the Platinum database. We show our method provides a very good correlation with experimental data (up to ρ = 0.67) and is effective in predicting a range of chemotherapeutic, antiviral and antibiotic resistance mutations, providing useful insights for genotypic screening and to guide drug development. mCSM-lig also provides insights into understanding Mendelian disease mutations and as a tool for guiding protein design. mCSM-lig is freely available as a web server at http://structure.bioc.cam.ac.uk/mcsm_lig.
authors.affiliation: Department of Biochemistry, Sanger Building, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, UK.|Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Avenida Augusto de Lima 1715, Belo Horizonte, 30190-002, Brazil.
authors.forename: Douglas E V
authors.initials: DE
authors.lastname: Pires
authors.affiliation: Department of Biochemistry, Sanger Building, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, UK.
authors.forename: Tom L
authors.initials: TL
authors.lastname: Blundell
authors.affiliation: Department of Biochemistry, Sanger Building, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, UK.
authors.forename: David B
authors.initials: DB
authors.lastname: Ascher
mesh_terms: D000474:Alkaptonuria / Q000188:drug therapy / Q000235:genetics; D019295:Computational Biology / Q000379:methods*; D003196:Computer Graphics; D016208:Databases, Factual; D030562:Databases, Protein; D004351:Drug Resistance / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics; D016313:Genes, abl / Q000235:genetics; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000235:genetics; D006801:Humans; D020125:Mutation, Missense; D017354:Point Mutation; D011506:Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D012984:Software
chemical_list: D011506:Proteins; D054852:Small Molecule Libraries; D054303:HIV Reverse Transcriptase