The Role of the Medicinal Chemist in the Drug Discovery Process: current status and future prospects. Winter 05
At the present time and perhaps more so than at any time in its history, the pharmaceutical industry in the US and, indeed, worldwide faces numerous major challenges that threaten its future ability to thrive. Despite the much heralded advances in currently and once fashionable areas such as ‘genome derived’ target identification (1) and combinatorial chemistry (2) and major investments in new technologies the industry has not been able, in general, to produce a steady supply of new NCEs (or finance clinical development of the number of compounds required to ensure continued growth and financial success) that are necessary to provide the funds to sustain overall organisational viability and research funding (3).
As a result, over the past few years major pharmaceutical companies have been consistently tinkering with their R&D paradigms in an attempt to improve their drug discovery process. Reductions of candidate attrition rate or identifying ‘losers’ earlier in the discovery process have been key themes4. What is the role of today’s medicinal chemist in all this? Several excellent reviews and/or opinions have appeared in the literature on this topic5 over the past few years. A number of these comment on older, traditional roles of chemists and will not be touched upon here.
In today’s discovery environment there is no question that the medicinal chemist needs to be more versatile than ever before and be able to work across scientific boundaries. They need to be able to think innovatively and outside the box. They need to be both willing to maintain and hone their given skill set while being open to embrace new techniques and innovations. The days are long gone when a chemist can expect to start and finish a career by finely handcrafting the elaborate synthesis of multi-step targets and feel that they have done a good job by producing 10-20 compounds a year. Gone are the days of ‘mindlessly’ making huge libraries of compounds for High Throughput Screening (HTS) that just add numbers to a collection. Quality of compounds, whether based on novelty, physicochemical properties or purity is now of paramount importance6. Today’s medicinal chemist is part of a team that handles essentially all the components of the drug discovery process. They need excellent communication and interpersonal skills in order to be able to function effectively as a part of a multi-functional and multi-dimensional project team that consists of biologists, computational chemists, structural biologists including x-ray crystallographers, high throughput screeners, chemoinformatics scientists, information management technologists, pharmacokineticists, toxicologists, etc. In order to work effectively with scientists from these other disciplines, they need to be able to acquire at least a rudimentary knowledge of these disciplines.
At this point, having set the stage for an evaluation of current and future roles of the chemist, let us take a tour through each part of the drug discovery process in order to see where the medicinal chemist plays a significant part.
From a synoptic perspective the current paradigm can be depicted in modular form as shown in Figure 1.
An initial part of the process involves one of the most critical components, namely target identification and validation7. The medicinal chemist is playing a larger role in this process of late. This is due, in part, to the current popularity of chemical genetics8, both forward and reverse, for the identification of pharmacologically active compounds from phenotypic screens. There are numerous successful examples of this approach. The role of the chemist in this module has been to provide novel compounds as pharmacologic probes. Diversity Oriented Synthesis (DOS), as propounded by Schreiber9, has been utilised as a tool to direct synthetic chemistry efforts towards a set of small molecules with properties unseen before. The role of the chemist in providing compounds for screening whether it be it high throughput, high content, fragment-based or phenotypic, is best covered under the Lead Identification/generation banner and has been under the spotlight over the past few years as companies have focused significant effort on improving the quality, diversity and size of their corporate screening collections. Numerous articles have been written on the ideal size and composition of a collection. Given that it has been postulated by Bohacek and colleagues10 that more than 1,060 molecules are synthesisable and that the Beilstein database from 1779 to the present contains only ~107 molecules, it is a tremendous challenge for the chemist to decide what molecules to make. To this end, the chemist should be familiar with contemporary structure-based design techniques11, protein structure12, and their associated privileged structures13. Virtual ligand screening techniques should also come into play wherever possible14. Knowledge of protein structure has facilitated the construction of numerous focused libraries of compounds targeted at kinases, GPCRs and nuclear hormone receptors15. Aside from DOS techniques, numerous approaches have been undertaken for the construction of libraries of diverse structures. Current thinking is that libraries of smaller size (100-250 members) based on a greater selection of chemotypes are more diverse and cover greater chemical space than libraries of large number of compounds constructed around a few chemotypes16.
Numerous innovative approaches have been adopted by medicinal chemists for the construction of such focused or diverse collections. Of particular note has been the utilisation of multiple component coupling reactions such as the Ugi and Passerini for the rapid and efficient construction of diverse screening sets centred on pharmaceutically relevant chemotypes. These reactions are particularly useful as they have the capability of delivering compounds of diverse structure in a single reaction step. This area has been reviewed extensively17. The work of Hulme and co-workers on the development of a Ugi/Deprotection/ Cyclisation (UDC) protocol that secured libraries of key heterocyclic pharmacophores such as dihydroquinoxazolinones, benzodiazepines, diketopiperazines is noteworthy. At Abbott, one of our approaches towards the production of novel, drug or lead-like compounds has been to incorporate latent reactivity into the inputs of Ugi-derived libraries. To this end we have used post-Ugi modification reactions such as the Heck reaction, the Huisgen triazole synthesis and the intramolecular nitrile oxide cyclisation reaction to produce novel heterocyclic scaffolds for inclusion in our corporate screening set18. These types of approaches highlight the considerable potential for synthetic creativity and innovation on the part of the synthetic/ medicinal chemist in the early stages of the drug discovery process. In addition, it would be remiss of the author not to mention the utility of natural products as potential sources of hits/leads. Many natural product aficionados are still bemoaning the de-emphasis of this avenue of research at the expense of combinatorial chemistry a number of years ago. This situation may change with a recent renaissance of this line of investigation19. The chemist must also be fully cognizant with other approaches to add useful compounds to the screening set and the interplay with related drug discovery disciplines such as fragnomics, or fragment-based drug discovery20 and concepts of both drug-like21 and lead-like22 structures which are critical to an understanding of what building blocks have the highest likelihood of being translated from hits to leads and subsequently, drug candidates. Chemists may well be involved in the process of synthesising libraries of compounds for corporate file enhancement that are to be used for HTS campaigns. Although many companies have contracted a substantial portion of this work out (India and China have been the beneficiaries of recent trends in how this process is managed23), a significant amount of work is still carried out by high throughput synthesis groups like the Glaxo SmithKline (GSK) compound factory initiative. Chemists in these groups need to be expert in automated chemistry techniques including parallel synthesis, which may be done in a variety of more or less sophisticated equipment including shaker blocks/liquid handlers, and automated platforms such as the ChemSpeed™, which has found utility in our laboratories. Much high throughput chemistry has been enabled by the use of polymer-supported reagents24. Ley’s group at Cambridge have been major players in advancing our knowledgebase in the area; however industrial groups such as that at GSK and our own High Throughput Organic Synthesis group at Abbott have also made significant contributions in developing effective and reliable standardised reaction protocols for a plethora of synthetic transformations ranging from simple amide bond forming reactions to palladium catalysed coupling reactions to the development of robust new routes to heterocyclic rings of pharmacological relevance. Chemists also need to be able to fully utilise microwave chemistry, which has come much into vogue over the past few years. The ability of microwave chemistry to improve productivity in the pharmaceutical laboratory is now a given. In addition, the optimisation and utilisation of parallel synthesis in the microwave25 will also provide a significant boost to the chemist’s ability to deliver large numbers of compounds in a timely manner.
Once hits are identified from high throughput screening (or other sources) the chemists may become involved in Hit to Lead (H2L) studies when hits from screens are effectively triaged and closely scrutinised for ability to serve as full blown lead compounds. Several companies, including AstraZeneca, have established separate H2L groups which, having been given relevant criteria for qualifications of a lead compound by the Therapeutic Area teams, thoroughly evaluate the potential of hits from HTS to fulfill these characteristics. These processes involve the assessment of a compound’s reactivity (false positive hit-target poison), patentability/freedom to operate issues around the structure and its congeners (known chemotype – numerous patents on chemotype for same or different biological targets?), biological or chemotype history (had it been optimised for another target previously internally or externally, are there possible off-target effects to be considered, was it purchased from commercial vendors), optimisability including physicochemical properties such as clogP, solubility, ligand efficiency26, chemical tractability and initial SAR studies. This process requires a advance members of these series to candidate status. As can be seen from Figure 2 this is a formidable challenge. The enormity of the problem does not exclusively reside in identifying compounds that effectively target ‘validated target’ proteins. Aside from the fact that these candidates should exhibit, ideally, pharmacokinetic properties commensurate with once a day dosing they must exhibit a superior safety profile. This means that it should avoid, as much as possible, hitting the multitude of other targets out there, particularly those that would give rise to undesired off-target related side-effects which could limit or preclude development.
Databases of ‘biological fingerprints’ of compounds and, indeed, chemotypes are now commercially available, eg CEREP’s Bioprint database, and these are being used to proactively predict potential off-target effects of compounds related to specific structural and/or mechanistic classes and potential development compounds31. Today’s chemist needs to be aware of these enabling tools. Also, on the topic of the assessment of off-target effects of compounds, the majority of practising medicinal chemists are now thoroughly acquainted with the need to avoid compounds that interact with hERG channels32, compounds that exhibit the potential for clastogenic or mutagenic activity in man and compounds that may act as inhibitors or inducers of any of the key cytochrome P450 class of enzymes, such as 3A4 or 2D6 that direct the hepatic metabolism of drugs and the potential drug-drug interactions33. The chemist should be familiar with possible metabolic ‘hotspots’ on molecules and with ways to modify them in order to alleviate or eliminate the problem. Many good reviews of this topic have appeared in the literature34 and computer programs for the prediction of potential sites of metabolism of small molecule drug candidates are currently being developed and commercialised. In a similar vein, interaction of drugs with drug transporters such as PgP is currently the topic of much interest and once again knowledge of this problem and potential solutions from a compound structure modification/manipulation standpoint is critical to the success of today’s chemist35. The above examples highlight the significant number of tools that the current practitioner must have in their arsenal of medicinal chemistry weapons. In this context it must be noted that considerable effort is currently being expended by ‘major pharma’ on approaches towards the identification of potential reactive metabolites of drug development candidates. As toxicity is now the major leading cause of attrition of compounds in the clinic, and indeed, on the market this issue is of paramount importance. As idiosyncratic toxicity is quite often identified late in the game and, in many cases, after a drug has been on the market a significant period of time it is absolutely critical to the success of the industry that these debacles, which can be financially paralysing are avoided. As mentioned above, the medicinal chemist can play a significant role in the solution to this problem by producing compounds that, if metabolised, are converted to relatively benign progeny of the parent. This area of research has been recently and excellently reviewed by, among others, Evans et al at Merck36.
Also, on the drug safety front, databases, of which many are currently commercially available, are being developed in order to allow the chemist access to data regarding the potential toxicity, including genotoxicity of classes of small molecules. Although needing much further work and input such collections may, in the future, provide a treasure trove of information for the chemist on structures and, more significantly, substructures to be avoided. The contemporary medicinal chemist must be technologically savvy and comfortable with all aspects of data integration and management. For example, he or she has to be able to manipulate, analyse and, hopefully, make sense of huge amounts of data, whether it be HTS, H2L, Structure Activity Relationship (SAR), Pharmacokinetic (PK), in vivo pharmacologic activity, or Structure Toxicity Relationships (STR). They need to be fully conversant with technology that allows them to do this, eg Spotfire™.
On a final note related to drug safety and the prediction of off-target effects the chemist has begun to play a significant role in the emerging area of chemical proteomics and metabolomics. Several proteomic strategies utilise synthetic chemistry to create tools and assays for the characterisation of protein samples of high complexity. These approaches include the development of chemical affinity tags to measure the relative expression level and post-translational modification of proteins in cell and tissue proteomes. In addition, recently, Cravatt and co-workers have reviewed the emerging field of activity-based protein profiling, which aims to synthesise and apply small molecule probes that monitor dynamics in protein function in complex proteomes37. Specific examples of efforts in the pharmaceutical industry include approaches to scan the proteome for targets of small molecule kinase inhibitors38.
In summary, let me assert that chemistry remains a truly discriminating and invaluable science that plays a critical role in the drug development process currently ongoing in the pharmaceutical industry. It is the scaffold on which all key components of the drug discovery paradigm are assembled and it is the engine that drives the other components of the machine. To illustrate this point, if we simply focus on one aspect of the chemist’s function one might argue that a company’s success at delivering clinical candidates will be hugely dependent upon the leads that it obtains. Most often these compounds are identified from corporate compound collections. These leads are produced by the chemists. They have to be produced and optimised creatively in order to provide all important intellectual property rights for the organisation. An organisation, it may be argued, is as good as its compound collection.
Looking into the crystal ball, as outlined above, one can only see medicinal chemoevolution proceeding in such a manner that it becomes more and more vital and indispensable to the future success of the industry. As for the chemists themselves, those that display flexibility, a willingness to work across boundaries and an ability to think outside of the box will thrive.
The author would like to thank Dr Jim Summers (Vice-President, Advanced Technologies, Abbott Laboratories) and Professor Les Mitscher (Department of Medicinal Chemistry, The University of Kansas) for valuable and insightful discussions and expert critique of this manuscript.
Dr Stevan Djuric is responsible for the Medicinal Chemistry Technology and Structural Chemistry groups at Abbott Laboratories. Their current efforts are focused on new initiatives in the areas of high throughput synthesis and purification and the design and construction of novel compound libraries for lead targeting and identification. During his tenure at Abbott Laboratories, Dr Djuric has been a Project Leader for groups in the Immunoscience, Metabolic Disease and Antiinfective areas. Several of these programmes have advanced compounds into clinical development including Abbott’s proprietary rapamycin analog used for its Zomaxx stent. Dr Djuric has more than 100 scientific publications, presentations and patents/applications pending. He has also given more than 20 invited lectures at universities and national meetings and, in addition, holds an Adjunct Professorship in the Department of Medicinal Chemistry at the University of Kansas.
It is clearly impossible, or at least impractical, to cite all the excellent work that has been published on the aforementioned topics. I have endeavored to provide key references that will allow the reader to track down further subject material of interest to them.
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2 Borman, S. Reducing time to drug discovery, C&E News 33-60 (1999). However, for a recent alternative view see Merritt,AT and Gerritz SW. Curr.Opin.Chem.Biol. 7 305-307 (2003).
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4 Milne, GM. Pharmaceutical productivity – the imperative for new paradigms, Ann.Rep.Med.Chem. 38 383-396 (2003).Also see www.biag.org (Article 4, 2005) for an analysis of the current cost of drug discovery and the key role that compound attrition plays in this cost.
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6 See, for example, Lipinski, C.A. Drug-like properties and the causes of poor solubility and poor permeability. J.Pharmacol.Toxic.Methods, 44 235-249 (2000), Hann, MM, Leach,AR, and Harper, G. Molecular complexity and and its impact on the probability of finding leads for drug discovery, J.Chem.Inf.Comput.Sci.41 856- 864 (2001),Vieth, M et al. Characteristic physical properties and structural fragments of marketed oral drugs J.Med. Chem. 47 224-232 (2004).
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13 See, for example, DeSimone, RW, Currie, KS, Mitchell,SA, Darrow, JW and Pippin,DA. Privileged structures: Application in drug discovery. Combinatorial Chemistry & High Throughput Screening 7 473-493 (2004) and references therein.
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