The Chemical Basis of Pharmacology

Molecular biology now dominates pharmacology so thoroughly that it is difficult to recall that only a generation ago the field was very different. To understand drug action today, we characterize the targets through which they act and new drug leads are discovered on the basis of target structure and function. Until the mid-1980s the information often flowed in reverse: investigators began with organic molecules and sought targets, relating receptors not by sequence or structure but by their ligands. Recently, investigators have returned to this chemical view of biology, bringing to it systematic and quantitative methods of relating targets by their ligands. This has allowed the discovery of new targets for established drugs, suggested the bases for their side effects, and predicted the molecular targets underlying phenotypic screens. The bases for these new methods, some of their successes and liabilities, and new opportunities for their use are described.

[1]  P. Jaccard,et al.  Etude comparative de la distribution florale dans une portion des Alpes et des Jura , 1901 .

[2]  R. Ahlquist,et al.  A study of the adrenotropic receptors. , 1948, The American journal of physiology.

[3]  F. Young.  Biochemistry , 1955, The Indian Medical Gazette.

[4]  A. M. Lands,et al.  Differentiation of Receptor Systems activated by Sympathomimetic Amines , 1967, Nature.

[5]  J. Black,et al.  Effects in man of histamine H 2 -receptor blockade by burimamide. , 1972, Lancet.

[6]  J. Black,et al.  Definition and Antagonism of Histamine H2-receptors , 1972, Nature.

[7]  G. Engel,et al.  Identification of serotonin M-receptor subtypes and their specific blockade by a new class of drugs , 1985, Nature.

[8]  Johnz Willett.  Similarity and Clustering in Chemical Information Systems , 1987 .

[9]  E. Myers,et al.  Basic local alignment search tool. , 1990, Journal of molecular biology.

[10]  D. Sibley,et al.  Cloning, Characterization, and Chromosomal Localization of a Human 5‐HT6 Serotonin Receptor , 1996, Journal of neurochemistry.

[11]  Yvonne C. Martin,et al.  Use of Structure-Activity Data To Compare Structure-Based Clustering Methods and Descriptors for Use in Compound Selection , 1996, J. Chem. Inf. Comput. Sci..

[12]  J. Bockaert,et al.  Pharmacological comparison between [3H]GR 113808 binding sites and functional 5-HT4 receptors in neurons. , 1996, European journal of pharmacology.

[13]  Thomas Lengauer,et al.  A fast flexible docking method using an incremental construction algorithm. , 1996, Journal of molecular biology.

[14]  Thomas L. Madden,et al.  Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. , 1997, Nucleic acids research.

[15]  E. sanders-Bush,et al.  Agonist Properties of N,N-Dimethyltryptamine at Serotonin 5-HT2A and 5-HT2C Receptors , 1998, Pharmacology Biochemistry and Behavior.

[16]  J. M. Kennedy,et al.  Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications. , 1998, NIDA research monograph.

[17]  B. Roth,et al.  The Multiplicity of Serotonin Receptors: Uselessly Diverse Molecules or an Embarrassment of Riches? , 2000 .

[18]  Ajay N. Jain.  Morphological similarity: A 3D molecular similarity method correlated with protein-ligand recognition , 2000, J. Comput. Aided Mol. Des..

[19]  Irwin D. Kuntz,et al.  Virtual Screening of Combinatorial Libraries across a Gene Family: in Search of Inhibitors of Giardia lamblia Guanine Phosphoribosyltransferase , 2001, Antimicrobial Agents and Chemotherapy.

[20]  Ruedi Stoop,et al.  An Ontology for Pharmaceutical Ligands and Its Application for in Silico Screening and Library Design , 2002, J. Chem. Inf. Comput. Sci..

[21]  J. Jenkins,et al.  A 3D similarity method for scaffold hopping from known drugs or natural ligands to new chemotypes. , 2004, Journal of medicinal chemistry.

[22]  S. Peroutka,et al.  Hallucinogenic drug interactions with neurotransmitter receptor binding sites in human cortex , 2004, Psychopharmacology.

[23]  J. A. Grant,et al.  A shape-based 3-D scaffold hopping method and its application to a bacterial protein-protein interaction. , 2005, Journal of medicinal chemistry.

[24]  Paul A Clemons,et al.  The Connectivity Map: Using Gene-Expression Signatures to Connect Small Molecules, Genes, and Disease , 2006, Science.

[25]  G. V. Paolini,et al.  Global mapping of pharmacological space , 2006, Nature Biotechnology.

[26]  Didier Rognan,et al.  sc-PDB: an Annotated Database of Druggable Binding Sites from the Protein Data Bank , 2006, J. Chem. Inf. Model..

[27]  Didier Rognan,et al.  In silico-guided target identification of a scaffold-focused library: 1,3,5-triazepan-2,6-diones as novel phospholipase A2 inhibitors. , 2006, Journal of medicinal chemistry.

[28]  Jian Zhang,et al.  Peptide deformylase is a potential target for anti‐Helicobacter pylori drugs: Reverse docking, enzymatic assay, and X‐ray crystallography validation , 2006, Protein science : a publication of the Protein Society.

[29]  R. Stevens,et al.  GPCR Engineering Yields High-Resolution Structural Insights into β2-Adrenergic Receptor Function , 2007, Science.

[30]  Xin Wen,et al.  BindingDB: a web-accessible database of experimentally determined protein–ligand binding affinities , 2006, Nucleic Acids Res..

[31]  A. Barabasi,et al.  Drug—target network , 2007, Nature Biotechnology.

[32]  Jian Wang,et al.  In Silico Elucidation of the Molecular Mechanism Defining the Adverse Effect of Selective Estrogen Receptor Modulators , 2007, PLoS Comput. Biol..

[33]  A. Bender,et al.  Modeling Promiscuity Based on in vitro Safety Pharmacology Profiling Data , 2007, ChemMedChem.

[34]  Justin Lamb,et al.  The Connectivity Map: a new tool for biomedical research , 2007, Nature Reviews Cancer.

[35]  Michael J. Keiser,et al.  Relating protein pharmacology by ligand chemistry , 2007, Nature Biotechnology.

[36]  A. Bender,et al.  Analysis of Pharmacology Data and the Prediction of Adverse Drug Reactions and Off‐Target Effects from Chemical Structure , 2007, ChemMedChem.

[37]  Johannes C. Hermann,et al.  Structure-based activity prediction for an enzyme of unknown function , 2007, Nature.

[38]  Tudor I. Oprea,et al.  WOMBAT and WOMBAT‐PK: Bioactivity Databases for Lead and Drug Discovery , 2008 .

[39]  John A. Tallarico,et al.  Integrating high-content screening and ligand-target prediction to identify mechanism of action. , 2008, Nature chemical biology.

[40]  Lei Xie,et al.  Detecting evolutionary relationships across existing fold space, using sequence order-independent profile–profile alignments , 2008, Proceedings of the National Academy of Sciences.

[41]  Tudor I. Oprea,et al.  Quantifying the Relationships among Drug Classes , 2008, J. Chem. Inf. Model..

[42]  P. Bork,et al.  Drug Target Identification Using Side-Effect Similarity , 2008, Science.

[43]  Bin Chen,et al.  Gaining Insight into Off-Target Mediated Effects of Drug Candidates with a Comprehensive Systems Chemical Biology Analysis , 2009, J. Chem. Inf. Model..

[44]  R. Solé,et al.  The topology of drug-target interaction networks: implicit dependence on drug properties and target families. , 2009, Molecular bioSystems.

[45]  M. Jackson,et al.  The Hallucinogen N,N-Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator , 2009, Science.

[46]  Michael J. Keiser,et al.  Off-target networks derived from ligand set similarity. , 2009, Methods in molecular biology.

[47]  SIMPLE : A Strategic Information Mining Platform for IP Excellence , 2009 .

[48]  Thierry Langer,et al.  In silico Target Fishing for Rationalized Ligand Discovery Exemplified on Constituents of Ruta graveolens , 2008, Planta medica.

[49]  Teruo Hayashi,et al.  When the Endogenous Hallucinogenic Trace Amine N,N-Dimethyltryptamine Meets the Sigma-1 Receptor , 2009, Science Signaling.

[50]  Wendy A. Warr,et al.  ChEMBL. An interview with John Overington, team leader, chemogenomics at the European Bioinformatics Institute Outstation of the European Molecular Biology Laboratory (EMBL-EBI) , 2009, J. Comput. Aided Mol. Des..

[51]  Philip E. Bourne,et al.  Drug Discovery Using Chemical Systems Biology: Repositioning the Safe Medicine Comtan to Treat Multi-Drug and Extensively Drug Resistant Tuberculosis , 2009, PLoS Comput. Biol..

[52]  M. Milik,et al.  Mapping adverse drug reactions in chemical space. , 2009, Journal of medicinal chemistry.

[53]  Jeremy L Jenkins,et al.  Chemogenomic analysis of safety profiling data. , 2009, Methods in molecular biology.

[54]  John P. Overington.  ChEMBL. An interview with John Overington, team leader, chemogenomics at the European Bioinformatics Institute Outstation of the European Molecular Biology Laboratory (EMBL-EBI). Interview by Wendy A. Warr. , 2009, Journal of computer-aided molecular design.

[55]  Michael J. Keiser,et al.  Predicting new molecular targets for known drugs , 2009, Nature.

[56]  G. Schneider,et al.  Model structure of APOBEC3C reveals a binding pocket modulating ribonucleic acid interaction required for encapsidation , 2009, Proceedings of the National Academy of Sciences.

[57]  S. Haggarty,et al.  Zebrafish Behavioral Profiling Links Drugs to Biological Targets and Rest/Wake Regulation , 2010, Science.

[58]  R. Tagliaferri,et al.  Discovery of drug mode of action and drug repositioning from transcriptional responses , 2010, Proceedings of the National Academy of Sciences.

[59]  Didier Rognan,et al.  Binding of Protein Kinase Inhibitors to Synapsin I Inferred from Pair-Wise Binding Site Similarity Measurements , 2010, PloS one.

[60]  Michael J. Keiser,et al.  A pilot study of the pharmacodynamic impact of SSRI drug selection and beta-1 receptor genotype (ADRB1) on cardiac vital signs in depressed patients: a novel pharmacogenetic approach. , 2010, Psychopharmacology bulletin.

[61]  Michael J. Keiser,et al.  Prediction and evaluation of protein farnesyltransferase inhibition by commercial drugs. , 2010, Journal of medicinal chemistry.

[62]  Christian Laggner,et al.  Rapid behavior—based identification of neuroactive small molecules in the zebrafish , 2009, Nature chemical biology.

[63]  Daylight Theory Manual , 2011 .