D Drug Discovery A Historical Perspective

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DRUG DISCOVERY, suppressants Cyclosporin A and FK 506 are ing site for chemotherapeutic agents first where new drugs are no longer generated. examples 12 15 Cyclosporin A was dis proposed by Paul Ehrlich has already been solely by the imagination of chemists but. covered as early as 1972 in a screening pro mentioned A more functional concept in result from a dialogue between biologists. gram for antimicrobial compounds 14 which the receptor serves as a switch that and chemists This dialogue centered on bio. Biochemistry influenced drug research in receives and generates specific signals and chemical mechanisms of action stems from. many ways The dominant concepts intro can be either blocked by antagonists or turned the understanding of biological structure and. duced by biochemistry were those of en on by agonists was introduced into pharma function and gives rise to the creation of. zymes and receptors which were empirically cology by J N Langley in 1905 19 A novel chemical structures Molecular biology. found to be good drug targets The descrip crucial further step in this direction was taken has exerted a profound influence on drug. tion and characterization of carboanhydrase by R P Ahlquist in his seminal paper on discovery allowing the concept of genetic. in 1933 16 was fortuitously followed by the adrenotropic receptors in which he proposes information to be dealt with in very concrete. discovery that sulfanilamide the active me the existence of two types of adrenergic re biochemical and chemical terms At first. tabolite of the sulfonamide sulfa drug Pron ceptors 20 The pharmacological character however the influence of molecular biology. tosil inhibited this enzyme and that this ef ization of receptors in almost all organs in appeared to be restricted to cloning and ex. fect led to an increase in natriuresis and the cluding the brain provided the basis for a pressing genes that encode therapeutically. excretion of water 17 Sulfanilamide gave large number of very diverse drugs block useful proteins. rise to better carboanhydrase inhibitors such ers 21 agonists 22 benzodiazepines The total number of protein drugs. as acetazolamide and later led to more effec which enhance the effects of aminobutyric largely recombinant proteins and monoclo. tive diuretics such as hydrochlorothiazide and acid and chloride flux by way of the benzo nal antibodies that are often referred to as. furosemide 18 There are structural geneal diazepine receptor 23 and monoclonal an biotech drugs currently amounts to 59. ogies that link sulfanilamide with more ad tibodies which block receptors of growth or 27 Recombinant proteins have become. vanced sulfonamides like sulfathiazole with differentiation factors on tumor cells 24 important additions to the therapeutic ar. sulfonylureas like tolbutamide used in the A comprehensive analysis of the drug tar mamentarium After some delay monoclo. treatment of type II diabetes mellitus and gets underlying current drug therapy under nal antibodies a specialized form of recom. with diuretics that are being used to treat taken in 1996 showed that present day ther binant protein arrived on the scene 28 In. edema glaucoma or essential hypertension apy addresses only about 500 molecular targets 1998 biotech products most of them re. Fig 2 According to the analysis cell membrane combinant proteins and monoclonal anti. Structural pathways such as the one receptors largely heterotrimeric GTP bind bodies accounted for 15 out of 57 drugs. shown in Fig 2 illustrate the fact that the ing protein G protein coupled receptors introduced worldwide 26 3 Among the. sequential development of different therapeu constitute the largest subgroup with 45 of 50 leading research based companies the. tic areas could well be interpreted as chemi all targets and enzymes account for 28 of corresponding figures were 7 out of 40. cal diversification that at first occurred spon all current drug targets Fig 3 25 26 17 5 29 The human genome contains. taneously After serendipitous biological 12 000 to 14 000 genes encoding secreted. findings had been made certain prototypic The Influence of Molecular Biology on proteins Even if only 1 or 2 of these. structures were further derivatized in order to Drug Discovery proteins were to qualify as drugs there. obtain compounds with improved or altogeth Chemistry pharmacology microbiology would be between 120 and 280 novel ther. er novel effects and biochemistry helped shape the course apeutic proteins most of which still remain. The idea of a receptor as a selective bind of drug discovery and bring it to a level to be discovered and developed This figure. Fig 2 Sons of sulfanilamide,A schematic representation. of drugs that originated from,sulfanilamide A single chemi. cal motif gave rise to antibi,otics hypoglycemic agents. diuretics and antihyperten,sive drugs, www sciencemag org SCIENCE VOL 287 17 MARCH 2000 1961.
DRUG DISCOVERY, does not of course include monoclonal targeted by large pharmaceutical compa also would increase Based on my experi. antibodies which today are produced in nies at the end of the 20th century is con ence at Hoffmann La Roche and informa. three different ways They can be generated siderably smaller 40 If one accepts the tion provided from other sources 41 the. as mouse antibodies that are subsequently larger figure of 10 as representing the cor number of data points generated by large. humanized by recombination with human rect average of the number of the genes that screening programs at a pharmaceutical. antibody genes 30 32 Alternatively and contribute to a multifactorial disease then company amounted to roughly 200 000 at. perhaps preferably human antibodies can the total number of disease genes rele the beginning of the 1990s Data points are. be directly raised in nude mice grafted with vant from an industrial point of view may screening results describing the effect of. human immune cells 33 Finally antibod be 1000 Not every disease gene may in one compound at one concentration in a. ies can also be made by phage display itself be a feasible target However its particular test This figure rose to 5 to 6. techniques Huge libraries of human anti function will likely be linked to that of million at the middle of the decade and is. body genes in phages allow the production other proteins in physiological or patho presently approaching or even passing the. and subsequent optimization of a wide ar physiological circuits Assuming that the 50 million mark So far this several hun. ray of antibodies 34 36 In fact anti number of such linked proteins that con dredfold increase in the number of raw data. bodies may be more attractive from a stitute suitable targets for drug intervention has not yet resulted in a commensurate. therapeutic point of view than recombi is between 5 and 10 per disease gene we increase in research productivity As mea. nant cytokines or chemokines because they concluded that the number of potential drug sured by the number of new compounds. can be targeted to very specific struc targets may lie between 5 000 and 10 000 entering the market place the top 50 com. tures with almost surgical precision 25 In other words there are at least 10 panies of the pharmaceutical industry col. whereas many cytokines have evolved as times as many molecular targets that can be lectively have not improved their produc. proteins with redundant or pleiotropic ac exploited for future drug therapy than are tivity during the 1990s 42 43 There is of. tions Given the therapeutic success of being used today course the possibility that the average num. the interferons tissue plasminogen activa ber of compounds committed to develop. tor erythropoietin granulocyte macrophage Target Identification and Validation ment has increased in the last few years In. colony stimulating factor Herceptin Ritux The advent of genomic sciences rapid this case we would see a greater number of. imab and many others protein drugs are DNA sequencing combinatorial chemistry original new chemical entities entering the. likely to make many additional therapeutic cell based assays and automated high world markets within the next decade. contributions throughput screening HTS has led to a It is difficult to judge the success of. However the main promise of molecu new concept of drug discovery In this the new paradigm of drug discovery on the. lar biology for drug discovery lies in the new concept the critical discourse between basis of published data Some pharmaceu. potential to understand disease processes at chemists and biologists and the quality of tical companies have acknowledged that. the molecular genetic level and to deter scientific reasoning are sometimes replaced HTS has resulted in a large number of. mine the optimal molecular targets for drug by the magic of large numbers Large num hits 44 an impression that is corrob. intervention As mentioned current drug bers of hypothetical targets are incorporat orated by a number of recent publications. therapy is based on less than 500 molecular ed into in vitro or cell based assays and Fig 4 45 47 However some industry. targets Early work by the British geneticist exposed to large numbers of compounds leaders have expressed disappointment that. Sewall Wright indicated that the number of representing numerous variations on a few very few leads and development com. genes contributing to multifactorial traits chemical themes or more recently fewer pounds if any can be credited to the new. may not be very high 37 Current esti variations on a greater number of themes in drug discovery paradigm 44 On the one. mates based on Wright s work and more high throughput configurations It was hoped hand the meager results may be due to the. recent studies on hypertension and diabetes that this experimental design would be suit relatively short period during which the. mellitus in inbred strains of rats suggest able to identify many substances which new drug discovery paradigm has been se. this number to be between 5 and 10 38 can modify the targets in question Many riously implemented On the other hand. 39 If we count the nosological entities such hits compounds that elicit a posi the lack of meaningful results may indicate. that can be classified as multifactorial dis tive response in a particular assay would that the system has not yet been optimized. eases and include only those that pose a then give rise to more leads i e com What might have gone wrong during this. major medical problem in the industrial pounds that continue to show the initial initial phase. world on account of their prevalence and positive response in more complex models Two reasons come to mind one relating. severity we arrive at a figure between 100 cells animals in a dose dependent man to biology the other to chemistry The fact. and 150 In fact the repertoire of diseases ner Eventually the number of compounds that targets can be hypothetically associat. ed with certain diseases e g leptin or the,leptin receptor with obesity 48 the low. Fig 3 Molecular targets of drug density lipoprotein receptor with atheroscle. therapy Classification according rosis 49 complement receptors with in. to biochemical criteria Based on, a modern standard work of phar flammation 50 or interleukin 4 IL 4 with. macology the molecular targets allergic diseases 51 does not mean that. of all known drugs that have they represent suitable intervention levels for. been characterized as safe and new drugs They need validation a stepwise. effective have been collected process in which the role of a hypothetical. and listed according to their bio target in relation to a disease phenotype is. chemical nature 62,understood There are several levels of target. validation The credibility of a target de,pends on the complexity and disease rele.
vance of the model in which the target is,tested Reproducible and dose dependent. 1962 17 MARCH 2000 VOL 287 SCIENCE www sciencemag org. DRUG DISCOVERY, phenotypic changes in isolated cells elicited termed its affinity fingerprint The similarity of Eventually the structure of well validated. by a compound that modifies the target con affinity fingerprints has been shown to correlate old and new targets should be able to guide. stitute the lowest level of validation If phe with the biological activities of druglike sub the chemical effort directed at new drugs The. notypic changes can reproducibly be induced stances 55 novel approaches mentioned above all aim at. in an animal model that represents at least Improvements in structural biology more this objective. some disease relevant mechanisms the de specifically in nuclear magnetic resonance. gree of validation is higher The credibility of spectroscopy robotic crystallization cryo The Institutional Basis of Drug. a target grows with the number of relevant genic crystal handling x ray crystallography Research Will Change. animal models in which target modifications and high speed computing have greatly facil History does not repeat itself at least not. lead to the desired phenotypic changes Of itated protein structure determination 56 in a simple and linear way Nevertheless. course the highest degree of validation lies in 57 Indeed technological advances have pro there are parallels between the drug re. demonstrating that the modification of a tar pelled structural biology to a position where search in 1900 and in the year 2000 One. get e g the blocking of a receptor or the the elucidation of the three dimensional hundred years ago an alliance between. inhibition of an enzyme leads to the reversal structure of medically relevant proteins on a chemistry and pharmacology was created. Drug Discovery A Historical Perspective Ju rgen Drews Driven by chemistry but increasingly guided by pharmacology and the clinical sciences drug research has contributed more to the progress of medicine during the past century than any other scienti c factor The advent of molecular biology and in particular of genomic sciences is having a deep impact on drug discovery Recombinant

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