Perspective

IUPAC defined in 1998 Medicinal Chemistry as a chemistry-based discipline, also involving aspects of biological, medical and pharmaceutical sciences. It is concerned with the invention, discovery, design, identification and preparation of biologically active compounds, the study of their metabolism, the interpretation of their mode of action at the molecular level and the construction of structure-activity relationships¹. Is this still a valid definition or should it be modified? Within the past decade a lot of buzz words, such as chemogenomics, chemical genetics, chemical biology, pharmacoepigenetics, pharmacogenomics, chemical proteomics, systems chemical biology, chembioinformatics, came up which claim to be independent fields or disciplines related to drug discovery and development. With this perspective we would like to provoke a discussion on the future role of medicinal chemistry in the drug discovery and development process as well as give some thoughts on its definition.

The Royal Society of Chemistry defined Chemical biology as both the use of chemistry to advance a molecular understanding of biology and the harnessing of biology to advance chemistry². It is obvious that there is a great deal of overlap between these two scientific fields. Certainly the design, synthesis and characterisation of chemical probes that are used to study and manipulate biological systems, is best performed by experienced medicinal chemists in the classical definition.

However, one needs to be aware that good drugs and good chemical probes must meet different criteria³. Therefore the focus of a medicinal chemist in classical medicinal chemistry or in chemical biology will be different. Potency is important in both cases, but after that the requirements diverge significantly. Drugs must prove themselves in clinical trials with a desirable clinical outcome. Next to their pharmacodynamic properties, favourable pharmacokinetic parameters and absence of toxicology are required. The degree of selectivity of a drug for a particular protein target doesn’t really matter, as long as the phenotypic outcome is obtained. On the other hand, high selectivity is absolutely essential for a chemical probe, if one intends to make firm mechanistic conclusions during target profiling experiments. Chemical proteomics is an emerging discipline essential to determine the absolute target selectivity of chemical probes. Another difference between good drugs and good chemical probes is the nature of the interaction with the target. There is a strong bias in pharmaceutical industry that irreversible inhibitors would have unfavourable toxicity profiles (although numerous examples prove the contrary). For an irreversible chemical probe, the long lasting chemical knock down of a biological target will establish the relationship between a molecular target and the broader biological consequences of modulating the target. In this respect, the use of chemical probes in target validation mimics more closely the phenotypic outcome of the drugs that will be developed than genomic and genetic methods. Needless to say, that in order to reach firm conclusions the chemical probes will have to meet certain quality criteria. ⁴

The art of designing, synthesizing and characterising good quality chemical probes is an exciting challenge for medicinal chemistry. Especially medicinal chemists in the academic community should rise to this challenge since they often have state-of-the-art proteomic facilities at their disposal. This is in contrast with the lack of expertise and infrastructure to carry out ADME/Tox studies for drug discovery in most academic environments. This part of chemical biology is an area of pre-competitive chemistry that will greatly benefit from public-private collaborations and that should be supported by e.g. the Innovative Medicines Initiative (IMI) from the EU.

Chemogenomics, in its broadest sense, has been defined as the discovery and description of all possible drugs to all possible targets⁵. This is far beyond any reality, but in a more realistic scenario still should lead to the identification of ligands for all important proteins. With this definition chemogenomics makes a claim that touches the central aim of medicinal chemistry. However, statements like those above by no means account for the complexity of any drug discovery attempt. Generating selective agonists for GPCRs or highly selective inhibitors of ABC-transporters remains quite challenging and is far from being solved. A somewhat different definition of chemogenomics is that it refers to the perturbation of biological systems with the help of small molecules, thus gaining a holistic understanding of the interaction of these molecules with complex biological systems. This emphasises the more technological part of chemogenomics with its automation and miniaturisation attempts and is more in line with all the other “-omics” approaches. According to this definition, chemogenomics is thought to help to identifying the respective molecular targets of these compounds. Therefore, rather than following the long lasting paradigm of starting with the target to find the drug, chemogenomics should generate drugable targets⁶. Implementation of these technologies certainly will aid in our understanding how drugs work. With the few of a medicinal chemist, chemogenomics provides new tools and techniques which will support the medicinal chemist scaling his or her lead generation and –optimisation capabilities from single experiences towards a more broader and systematic understanding of the interaction of small molecules with biological systems. Being per se molecular driven, also chemogenomics has a lot of overlap with medicinal chemistry and thus offers great opportunities for our involvement.

These are two examples of new fields of research, which have been established and which have considerable overlap with medicinal chemistry and in some cases even have been started out of “classical” medicinal chemistry. These new research fields have a merit of their own, but also contribute to the continuous development of what medicinal chemistry is, and what future drugs should look like. While classical drug discovery and development and understanding structure activity relationships are still the core of medicinal chemistry, the field has developed a lot, including much more than the classical definition indicates.

In 2008, the governing board of IMI – The Innovative Medicines Initiative – approved the strategic research agenda of this World’s largest public private partnership with a volume of 2 billion € for the next 7 years⁷. The IMI Research Agenda is a multiannual plan developed by the European Technology Platform on Innovative Medicines which identified principal research bottlenecks in the biopharmaceutical R&D process and sets forth recommendations to overcome these bottlenecks by focusing on four areas: predicting safety, predicting efficacy, knowledge management, and education and training. Main disease areas targeted are cancer, brain disorders, metabolic disease, inflammation and infectious diseases.

The research projects proposed by IMI are broad and multi-disciplinary and thus cannot be carried out by one company or within one member state. One main characteristic of IMI is that projects are also ‘precompetitive’ for the pharmaceutical industry. Companies (including SMEs), academics, regulators and patients need to come together to share resources and expertise to address the challenges of drug discovery and development (www.imi-europe.org). Results and the knowledge and capabilities gained from performing such projects should be made available to the entire public and private sector. For example, the call for an open pharmacological space (knowledge management call round 2) should lead to an open data open access system where you can answer questions like “give me all compounds inducing cholestasis and their profiles at liver transporters” just with typing in one query! This will revolutionise the way how data can be mined in medicinal chemistry projects.

There was a lot of discussion within EFMC that IMI is not made for medicinal chemists, as medicinal chemistry is considered a core discipline in drug discovery, thus being purely competitive. However, as outlined above, medicinal chemistry knowledge is required in a lot of areas considered to be precompetitive, such as chemical biology and chemogenomics. Thus, there are many opportunities for medicinal chemists and the projects approved in the first call showed already that there is plenty of space for medicinal chemistry groups.

The science of medicinal chemistry has been used since more than 100 years for the discovery and development of new safe medicines. The field has become increasingly dynamic and medicinal chemists face the challenge of rapidly evolving new technologies. One of the next large steps will be the “virtualisation” of the field. The Swiss branch office of PricewaterhouseCoopers recently published an analysis that greater use of new technologies to virtualise the research process and accelerate clinical development will reduce the number of clinical studies by 40% and the number of patients in clinical studies by 65%. Whether real or virtual, finally it comes down to chemical entities and their interactions, which are driven by the basic laws of physicochemistry. EFMC is ready to take the challenge of being the central hub for these developments. With its symposia, short courses and schools, its newsletter and now also with MedChemComm, EFMC provides perfect conditions for exchanging and promoting new ideas, exploring new grounds and moving beyond established thinking!

Koen Augustyns & Gerhard F. Ecker

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(1) http://www.chem.qmul.ac.uk/iupac/medchem/
(2) http://www.rsc.org/ScienceAndTechnology/Policy/
Bulletins/Issue3/Chemicalbiology.asp
(3)Kodadek, T. Rethinking screening. Nat. Chem. Biol. 2010, 6, 162-165
(4) Frye, S.V. The art of the chemical probe Nat. Chem. Biol. 2010, 6, 159-161
(5) Müller, G.; Kubinyi, H. Chemogeniomics in Drug Discovery. Wiley-VCH 2005
(6) Szymovski, D.E. Chemical genomics versus orthodox drug development. Drug Discovery Today 2003, 8, 157-159
(7) http://imi.europa.eu