Strategies in the Search for New Lead Compounds or Original Working Hypotheses

This chapter is presenting the various strategies used to find pertinent compounds as starting points for optimization up to a drug. The discovery strategies from the historical ones to the most modern approaches are reviewed. They consist into mainly five approaches: the improvement of already existing drugs, the systematic screening, the exploitation of observed biological activities, the attempts towards rational design and the target protein structure-based approaches. These strategies are not mutually exclusive and can be appropriately applied and combined.

[1]  A. Bull,et al.  Biodiversity as a source of innovation in biotechnology. , 1992, Annual review of microbiology.

[2]  Olivier Sperandio,et al.  Rationalizing the chemical space of protein-protein interaction inhibitors. , 2010, Drug discovery today.

[3]  P. Kollman,et al.  Pathways to a protein folding intermediate observed in a 1-microsecond simulation in aqueous solution. , 1998, Science.

[4]  M. Angell.  The Truth About the Drug Companies: How They Deceive Us and What to Do About It , 2004 .

[5]  Harren Jhoti,et al.  High-throughput crystallography for lead discovery in drug design , 2002, Nature Reviews Drug Discovery.

[6]  C. Niemegeers,et al.  Chemistry and pharmacology of CNS depressants related to 4-(4-hydroxy-phenylpiperidino)butyrophenone. I. Synthesis and screening data in mice. , 1959, Journal of medicinal and pharmaceutical chemistry.

[7]  F E Cohen,et al.  Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Y. Ohta,et al.  Studies on disease-modifying antirheumatic drugs: synthesis of novel quinoline and quinazoline derivatives and their anti-inflammatory effect. , 1996, Journal of medicinal chemistry.

[9]  Robert Bywater,et al.  Improving the Odds in Discriminating "Drug-like" from "Non Drug-like" Compounds , 2000, J. Chem. Inf. Comput. Sci..

[10]  Y Pommier,et al.  Synthesis of new indeno[1,2-c]isoquinolines: cytotoxic non-camptothecin topoisomerase I inhibitors. , 2000, Journal of medicinal chemistry.

[11]  R J Lynch,et al.  Non-peptide fibrinogen receptor antagonists. 1. Discovery and design of exosite inhibitors. , 1992, Journal of medicinal chemistry.

[12]  S. Chong,et al.  Discovery of (R)-7-cyano-2,3,4, 5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3- (phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine (BMS-214662), a farnesyltransferase inhibitor with potent preclinical antitumor activity. , 2000, Journal of medicinal chemistry.

[13]  A Binnie,et al.  Efficient discovery of inhibitory ligands for diverse targets from a small combinatorial chemical library of chimeric molecules. , 1999, Biochemical and biophysical research communications.

[14]  J. Hughes,et al.  Physiochemical drug properties associated with in vivo toxicological outcomes. , 2008, Bioorganic & medicinal chemistry letters.

[15]  Mark T D Cronin,et al.  A review of the use of in silico methods to predict the chemistry of molecular initiating events related to drug toxicity , 2011, Expert opinion on drug metabolism & toxicology.

[16]  Timothy B. Stockwell,et al.  The Sequence of the Human Genome , 2001, Science.

[17]  Frederic D. Bushman,et al.  Lamellarin α 20-Sulfate, an Inhibitor of HIV-1 Integrase Active against HIV-1 Virus in Cell Culture , 1999 .

[18]  Ping Chen,et al.  Biphenylsulfonamide endothelin receptor antagonists. 4. Discovery of N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]- 2-yl]methyl]-N,3,3-trimethylbutanamide (BMS-207940), a highly potent and orally active ET(A) selective antagonist. , 2003, Journal of medicinal chemistry.

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

[20]  T. Hamilton,et al.  Synthesis and antihypertensive activity of substituted trans-4-amino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ols. , 1984, Journal of medicinal chemistry.

[21]  Cornel Catana,et al.  Strategies for small molecule library design. , 2014, Current pharmaceutical design.

[22]  N. Murugesan,et al.  The discovery of sulfonamide endothelin antagonists and the development of the orally active ETA antagonist 5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulf onamide. , 1994, Journal of medicinal chemistry.

[23]  W. Foye,et al.  Principles of medicinal chemistry , 1974 .

[24]  Robert A. Maxwell,et al.  Drug Discovery: A Casebook and Analysis , 1990 .

[25]  R L NOBLE,et al.  ROLE OF CHANCE OBSERVATIONS IN CHEMOTHERAPY: VINCA ROSEA * , 1958, Annals of the New York Academy of Sciences.

[26]  Sean Ekins,et al.  In silico repositioning of approved drugs for rare and neglected diseases. , 2011, Drug discovery today.

[27]  Olivier Sperandio,et al.  One hundred thousand mouse clicks down the road: selected online resources supporting drug discovery collected over a decade. , 2013, Drug discovery today.

[28]  C Garret,et al.  In vitro and in vivo inhibition by zopiclone of benzodiazepine binding to rodent brain receptors. , 1979, Life sciences.

[29]  L. Schiffer,et al.  Aromatic amino acids and modification of parkinsonism. , 1967, The New England journal of medicine.

[30]  R. Stevens,et al.  Global Efforts in Structural Genomics , 2001, Science.

[31]  Laurence Choulier,et al.  Validation of surface plasmon resonance screening of a diverse chemical library for the discovery of protein tyrosine phosphatase 1b binders. , 2012, Analytical biochemistry.

[32]  C G Wermuth,et al.  Aminopyridazines--an alternative route to potent muscarinic agonists with no cholinergic syndrome. , 1993, Farmaco.

[33]  D. Moller,et al.  Discovery of a potent, highly selective, and orally efficacious small-molecule activator of the insulin receptor. , 2000, Journal of medicinal chemistry.

[34]  Weida Tong,et al.  In silico drug repositioning: what we need to know. , 2013, Drug discovery today.

[35]  A. Endo,et al.  Compactin (ML-236B) and related compounds as potential cholesterol-lowering agents that inhibit HMG-CoA reductase. , 1985, Journal of medicinal chemistry.

[36]  C. Wermuth,et al.  SR 95191, a selective inhibitor of type A monoamine oxidase with dopaminergic properties. I. Psychopharmacological profile in rodents. , 1987, The Journal of pharmacology and experimental therapeutics.

[37]  Jayme L. Dahlin,et al.  The essential roles of chemistry in high-throughput screening triage. , 2014, Future medicinal chemistry.

[38]  M. Boyd,et al.  Some practical considerations and applications of the national cancer institute in vitro anticancer drug discovery screen , 1995 .

[39]  Andrew Simon Bell,et al.  Sildenafil (VIAGRATM), a potent and selective inhibitor of type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction , 1996 .

[40]  D. Rognan,et al.  Protein-based virtual screening of chemical databases. 1. Evaluation of different docking/scoring combinations. , 2000, Journal of medicinal chemistry.

[41]  John Crosby,et al.  Automated protein-ligand interaction screening by mass spectrometry. , 2012, Journal of medicinal chemistry.

[42]  Mark A. Murcko,et al.  Virtual screening : an overview , 1998 .

[43]  F. Al-Obeidi,et al.  Factor Xa inhibitors by classical and combinatorial chemistry , 1998 .

[44]  Mander,et al.  Beyond uHTS: ridiculously HTS? , 2000, Drug discovery today.

[45]  Maurizio Recanatini,et al.  The role of fragment-based and computational methods in polypharmacology. , 2012, Drug discovery today.

[46]  Pickett,et al.  Computational methods for the prediction of 'drug-likeness' , 2000, Drug discovery today.

[47]  T Y Shen,et al.  Perspectives in nonsteroidal anti-inflammatory agents. , 1972, Angewandte Chemie.

[48]  P. Leeson,et al.  The influence of drug-like concepts on decision-making in medicinal chemistry , 2007, Nature Reviews Drug Discovery.

[49]  D. E. Clark.  What has virtual screening ever done for drug discovery? , 2008, Expert opinion on drug discovery.

[50]  Schmid,et al.  "Scaffold-Hopping" by Topological Pharmacophore Search: A Contribution to Virtual Screening. , 1999, Angewandte Chemie.

[51]  B. Everitt,et al.  Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 receptor agonist , 1999, Nature.

[52]  Paul D. Leeson,et al.  The influence of the 'organizational factor' on compound quality in drug discovery , 2011, Nature Reviews Drug Discovery.

[53]  D W Cushman,et al.  Design of potent competitive inhibitors of angiotensin-converting enzyme. Carboxyalkanoyl and mercaptoalkanoyl amino acids. , 1977, Biochemistry.

[54]  J. Baell,et al.  New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. , 2010, Journal of medicinal chemistry.

[55]  Nicholas H Oberlies,et al.  Fingolimod (FTY720): a recently approved multiple sclerosis drug based on a fungal secondary metabolite. , 2011, Journal of natural products.

[56]  T. Hamilton,et al.  Comparison of the effects of BRL 34915 and verapamil on electrical and mechanical activity in rat portal vein , 1986, British journal of pharmacology.

[57]  G. Rishton.  Nonleadlikeness and leadlikeness in biochemical screening. , 2003, Drug discovery today.

[58]  D. Bojanic,et al.  Impact of high-throughput screening in biomedical research , 2011, Nature Reviews Drug Discovery.

[59]  I L Buxton,et al.  NG-nitro L-arginine methyl ester and other alkyl esters of arginine are muscarinic receptor antagonists. , 1993, Circulation research.

[60]  Camille G. Wermuth.  Possible Alternatives to High‐Throughput Screening , 2006 .

[61]  Jean Thuillier,et al.  Les dix ans qui ont changé la folie , 1981 .

[62]  J. G. Vinter,et al.  Scaffold hopping with molecular field points: identification of a cholecystokinin-2 (CCK2) receptor pharmacophore and its use in the design of a prototypical series of pyrrole- and imidazole-based CCK2 antagonists. , 2005, Journal of medicinal chemistry.

[63]  M. Hann,et al.  Finding the sweet spot: the role of nature and nurture in medicinal chemistry , 2012, Nature Reviews Drug Discovery.

[64]  S. Carr,et al.  Orexins and Orexin Receptors: A Family of Hypothalamic Neuropeptides and G Protein-Coupled Receptors that Regulate Feeding Behavior , 1998, Cell.

[65]  Y.Z. Chen,et al.  Ligand–protein inverse docking and its potential use in the computer search of protein targets of a small molecule , 2001, Proteins.

[66]  Maxwell D Cummings,et al.  Universal Screening Methods and Applications of ThermoFluor® , 2006, Journal of biomolecular screening.

[67]  L. Sternbach.  The benzodiazepine story. , 1983, Journal of psychoactive drugs.

[68]  H. Böhm,et al.  Discovery and optimization of a novel class of orally active nonpeptidic endothelin-A receptor antagonists. , 1996, Journal of medicinal chemistry.

[69]  B K Shoichet,et al.  Structure-based discovery and in-parallel optimization of novel competitive inhibitors of thymidylate synthase. , 1999, Chemistry & biology.

[70]  Gisbert Schneider,et al.  Virtual screening and fast automated docking methods. , 2002, Drug discovery today.

[71]  D M Leonard,et al.  Ras farnesyltransferase: a new therapeutic target. , 1997, Journal of medicinal chemistry.

[72]  C. Wermuth.  The Sosa approach: An alternative to high-throughput screening , 2001 .

[73]  Andrew L. Hopkins,et al.  Chemical Tools for Indications Discovery , 2005 .

[74]  P. Janssen,et al.  The evolution of the butyrophenones, haloperidol and trifluperidol, from meperidine-like 4-phenylpiperidines. , 1965, International review of neurobiology.

[75]  Adrian Whitty,et al.  The resurgence of covalent drugs , 2011, Nature Reviews Drug Discovery.

[76]  V. Cryns,et al.  Caspases as targets for anti-inflammatory and anti-apoptotic drug discovery. , 2000, Journal of medicinal chemistry.

[77]  J. Languillon,et al.  WHO co-ordinated short-term double-blind trial with thalidomide in the treatment of acute lepra reactions in male lepromatous patients. , 1971, Bulletin of the World Health Organization.

[78]  L. Honigberg,et al.  Discovery of Selective Irreversible Inhibitors for Bruton’s Tyrosine Kinase , 2007, ChemMedChem.

[79]  O. Hornykiewicz,et al.  Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the human brain and their behavior in diseases of the extrapyramidal system. , 1960, Parkinsonism & related disorders.

[80]  D. Sall,et al.  Modern phenotypic drug discovery is a viable, neoclassic pharma strategy. , 2012, Journal of medicinal chemistry.

[81]  Joseph C. Lin.  Rule of Three: a case of discrimination against certain authors caused by the cataloging rules , 1985 .

[82]  Ta-Jyh Lee,et al.  Synthesis, SARs and therapeutic potential of HMG-CoA reductase inhibitors , 1987 .

[83]  V. Poroikov,et al.  Top 200 Medicines: Can New Actions be Discovered Through Computer-aided Prediction? , 2001, SAR and QSAR in environmental research.

[84]  G. Klebe,et al.  Statistical potentials and scoring functions applied to protein-ligand binding. , 2001, Current opinion in structural biology.

[85]  Anders Wallqvist,et al.  Classification of scaffold-hopping approaches. , 2012, Drug discovery today.

[86]  Wolfgang Jahnke,et al.  Solution Conformations and Dynamics of ABL Kinase-Inhibitor Complexes Determined by NMR Substantiate the Different Binding Modes of Imatinib/Nilotinib and Dasatinib*♦ , 2008, Journal of Biological Chemistry.

[87]  C Cotrel,et al.  The pharmacology of cyclopyrrolone derivatives acting at the GABAA/benzodiazepine receptor. , 1992, Advances in biochemical psychopharmacology.

[88]  C. Wiesmann,et al.  The discovery of first-in-class drugs: origins and evolution , 2014, Nature Reviews Drug Discovery.

[89]  A. Sali,et al.  Large-scale protein structure modeling of the Saccharomyces cerevisiae genome. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[90]  Ramesha,et al.  How many leads from HTS? - Comment. , 2000, Drug discovery today.

[91]  M. Wigglesworth,et al.  Orphan seven transmembrane receptor screening. , 2006, Ernst Schering Foundation symposium proceedings.

[92]  L. Goodman,et al.  The Pharmacological Basis of Therapeutics , 1941 .

[93]  R. D. Dyer,et al.  Synthesis, structure-activity relationships, and in vivo evaluations of substituted di-tert-butylphenols as a novel class of potent, selective, and orally active cyclooxygenase-2 inhibitors. 1. Thiazolone and oxazolone series. , 1999, Journal of medicinal chemistry.

[94]  Emanuele Perola,et al.  An analysis of the binding efficiencies of drugs and their leads in successful drug discovery programs. , 2010, Journal of medicinal chemistry.

[95]  W. Pitt,et al.  Heteroaromatic rings of the future. , 2009, Journal of medicinal chemistry.

[96]  Andy Vinter,et al.  Molecular Field Extrema as Descriptors of Biological Activity: Definition and Validation , 2006, J. Chem. Inf. Model..

[97]  W. Sneader.  Drug prototypes and their exploitation , 1996 .

[98]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[99]  H LABORIT,et al.  [A new vegetative stabilizer; 4560 R.P..]. , 1952, La Presse medicale.

[100]  F. Monsma,et al.  High-affinity, non-peptide agonists for the ORL1 (orphanin FQ/nociceptin) receptor. , 2000, Journal of medicinal chemistry.

[101]  I. S. Johnson,et al.  Antitumor principles derived from Vinca rosea Linn. I. Vincaleukoblastine and leurosine. , 1960, Cancer research.

[102]  Romualdo Benigni,et al.  Mechanisms of chemical carcinogenicity and mutagenicity: a review with implications for predictive toxicology. , 2011, Chemical reviews.

[103]  T. Willson,et al.  The PPARs: from orphan receptors to drug discovery. , 2000, Journal of medicinal chemistry.

[104]  D. Robertson,et al.  Corticotropin releasing factor (CRF) receptor modulators: progress and opportunities for new therapeutic agents. , 2000, Journal of medicinal chemistry.

[105]  M B Neuworth,et al.  Synthesis and hypocholesterolemic activity of alkylidenedithio bisphenols. , 1970, Journal of medicinal chemistry.

[106]  G. Muirhead,et al.  Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. , 1996, International journal of impotence research.

[107]  Harren Jhoti,et al.  The 'rule of three' for fragment-based drug discovery: where are we now? , 2013, Nature Reviews Drug Discovery.

[108]  Jonas Boström,et al.  Follow-on drugs: how far should chemists look? , 2011, Drug discovery today.

[109]  Jessica Friedman,et al.  A Kinase‐focused Compound Collection: Compilation and Screening Strategy , 2006, Chemical biology & drug design.

[110]  Lahana,et al.  How many leads from HTS? , 1999, Drug discovery today.

[111]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings , 1997 .

[112]  H Matter,et al.  Random or rational design? Evaluation of diverse compound subsets from chemical structure databases. , 1998, Journal of medicinal chemistry.

[113]  C. Wermuth.  Selective optimization of side activities: another way for drug discovery. , 2004, Journal of medicinal chemistry.

[114]  Peter Ertl,et al.  Bioisosteric Replacement and Scaffold Hopping in Lead Generation and Optimization , 2010, Molecular informatics.

[115]  R Abagyan,et al.  High-throughput docking for lead generation. , 2001, Current opinion in chemical biology.

[116]  Y. Shu,et al.  BMS-192548, a tetracyclic binding inhibitor of neuropeptide Y receptors, from Aspergillus niger WB2346. II. Physico-chemical properties and structural characterization. , 1995, The Journal of antibiotics.

[117]  M. Gleeson.  Generation of a set of simple, interpretable ADMET rules of thumb. , 2008, Journal of medicinal chemistry.

[118]  Stephen T. C. Wong,et al.  Toward better drug repositioning: prioritizing and integrating existing methods into efficient pipelines. , 2014, Drug discovery today.

[119]  Allen B. Reitz,et al.  α-Substituted N-(Sulfonamido)alkyl-β-aminotetralins: Potent and Selective Neuropeptide Y Y5 Receptor Antagonists , 2000 .

[120]  T. Davies,et al.  Fragment screening using X-ray crystallography. , 2012, Topics in current chemistry.

[121]  C. Wermuth,et al.  3-aminopyridazine derivatives with atypical antidepressant, serotonergic, and dopaminergic activities. , 1989, Journal of medicinal chemistry.

[122]  I. S. Johnson,et al.  THE VINCA ALKALOIDS: A NEW CLASS OF ONCOLYTIC AGENTS. , 1963, Cancer research.

[123]  P B Jones,et al.  A new class of antituberculosis agents. , 2000, Journal of medicinal chemistry.

[124]  D. Swinney,et al.  How were new medicines discovered? , 2011, Nature Reviews Drug Discovery.

[125]  György M Keseru,et al.  Hit discovery and hit-to-lead approaches. , 2006, Drug discovery today.

[126]  C. Wermuth.  Search for new lead compounds: The example of the chemical and pharmacological dissection of aminopyridazines , 1998 .

[127]  C. Wermuth,et al.  SR 46559 A and related aminopyridazines are potent muscarinic agonists with no cholinergic syndrome , 1992 .