Selina Y. L.
Holbrook
and
Sylvie
Garneau-Tsodikova
*
University of Kentucky, 789 South Limestone Street, Lexington, KY, 40536-0596 USA. E-mail: sylviegtsodikova@uky.edu
First published on 16th August 2017
Medicinal chemistry is a scientific discipline that has progressed rapidly over the last few decades. Facilitated by the technological advancement, the early understanding of medicinal chemistry as “synthesizing bioactive molecules” has become the connecting bridge of a variety of related scientific disciplines. This opinion article will guide you through a brief evolution of this discipline and discuss what medicinal chemistry has evolved to be in this era.
Based on the definitions currently available and the answers that we gathered, a simplified definition would be “the design and synthesis of biologically active molecules to address unmet medical needs”. However, this oversimplification ignores the larger historical context of medicinal chemistry and its ongoing evolution. To truly understand this discipline, we need to examine its past, present, and future to determine how it has come to encompass many different scientific domains, and how it is still shaping the world today.
During the Renaissance period, Paracelsus urged the early alchemists to discover the chemical essence to develop chemical medicines, especially the inorganic components such as mercury and antimony, forming a primitive idea of “active ingredients”. The French courts used to forbid the utilization of chemistry in medicine until Louis XIV was cured of chronic digestive problems with an antimony purge.5
World War II is a turning point when the definition of medicinal chemistry developed. After World War II, our advancement in the understanding of pharmacology at the molecular level made it possible to express the biological activity of a compound as quantifiable molecular properties. For example, an IC50 represents a substance's ability to inhibit its target. At the genesis of rational drug design, scientists gradually began to manipulate various parts of the molecules and observe the resulting changes in their biological activities. This allowed scientists to determine the crucial structural features of a molecule that contribute to its biological activity. This assay later developed into popular and informative studies called structure–activity relationship studies, which are still a mainstream technique used in the drug discovery and development processes today and often equated by many to medicinal chemistry itself.
Our repertoire of potential drug candidates is no longer limited to small molecules but has expanded to biologics that used to be considered exceedingly complicated as drugs. These include, but are not limited to, protein therapy, biological probes and linkers, and antibody-drug conjugates (Ley and Meanwell). Additionally, some pathology has been proven to require multi-protein interactions or complexes. In such cases, developing new classes of molecules that promote or disrupt the formation of multi-protein complexes has been a new forefront in medicinal chemistry (Spielmann). Alternative methodologies, such as exploiting natural product biosynthesis, allow us to access medically relevant molecules that are produced by various organisms while the use of chemical probes help us explore biochemically important processes (Van Lanen). Medicinal chemists are no longer just mixing chemicals to make new drugs. They are utilizing the power of Nature to chemoenzymatically generate new compounds (Garneau-Tsodikova).
Even though most people today still consider medicinal chemistry as the design and synthesis of biologically active molecules, no one would deny that medicinal chemistry has evolved to be the center of a vast variety of related scientific fields. Medicinal chemists connect the communities of analytical chemists, computational chemists, biochemists, chemical biologists, molecular biologists, cell biologists, structural biologists, microbiologists, pharmacologists, toxicologists, and translational medicine experts. They direct the orchestra of medicinal chemistry to collaboratively produce a harmonious composition that generates solutions to health related problems (López Rodríguez) (Fig. 1).
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Fig. 1 A cartoon showing how medicinal chemists orchestrate the discovery of new molecules to improve health by coordinating efforts amongst numerous disciplines. |
Historically, we have chemists, but now we have a plethora of subfields in chemistry: (bio)organic, (bio)inorganic, biological, physical, theoretical, analytical, material, and nuclear chemistry. All of these can make molecules that are active, but a medicinal chemist makes an active compound into a drug (Garneau-Tsodikova). Medicinal chemists have the additional training/expertise that enables them to take those next steps in developing a drug product from a molecule with in vitro activity (Garcia).
Indeed, the innovation of new technologies has sparked imagination and creativity amongst scientists, and made possible what was previously only fantasy. However, even in the Omics era, one should never forget how it is the structure of a molecule, the structure engineered during design and synthesis, that is ultimately responsible for a molecule's activity, side effects, and attrition (or lack of attrition) in clinical states (Bottegoni). Medicinal chemistry joins experts from various fields into a single army, fighting for the common good. Although challenges still exist and await improvement, we use our creativity and collaborative efforts to overcome such shortfalls. For instance, the complex human biology and its countless interconnected biological pathways can make targeting a specific molecule rather difficult, resulting in undesirable off-target effects. However, even these off-target effects can be beneficial for the development of new medicines. Even though Viagra was originally developed for blood pressure control, scientists observed a common side effect, which was later exploited for patients with erectile dysfunction.7 Additionally, the development of computational chemistry has provided valuable guidance to rational drug design and yielded successful medicines, such as Gleevec, a treatment for a specific type of leukemia.8 Nevertheless, such cases are relatively sparse and more/better computational models need to be developed (Ngo).
Medicinal chemistry is a precise science and a heavily data driven discipline (Congreve, Thomas). In order to make great medicinal chemistry, one needs to rely on the accuracy of previous discoveries that have provided massive amount of precious information and databases for the current medicinal chemists as a solid foundation to move forward. Medicinal chemistry is also an art where the artist uses a subtle mixture of knowledge, experimental learning, creativity, intuition, boldness, and serendipity to paint the right canvas (Jung and Radi). Medicinal chemistry is an adventure, a treasure hunt that seeks to offer us higher life quality. The treasure often lies outside the box. Medicinal chemistry is hope for people fighting against diseases (Arai) with medicinal chemists being the front-line solders with an up-lifting attitude.
Industry | |
Yves P. Auberson | Novartis, Switzerland |
Miles Congreve | Heptares, UK |
Pascal George | Consultant, former Sanofi-Aventis, France |
Laurence Jung | Prestwick Chemical, USA |
Nicholas Meanwell | Bristol-Myers Squibb, USA |
Gordon Saxty | Fidelta, Croatia |
Uli Stilz | Novo Nordisk, Denmark |
Andrew Thomas | Roche, Switzerland |
Ming-Qiang Zhang | Amgen, Shanghai, China |
Academia | |
Experienced researchers/professors | |
Midori Arai | Chiba University, Japan |
Timor Baasov | Israel Institute of Technology, Israel |
Giovanni Bottegoni | Istituto Italiano di Tecnologia, Italy |
Young-Tae Chang | POSTECH, Korea |
Frank Dekker | University of Groningen, Netherlands |
Stephen Frye | University of North Carolina at Chapel Hill, USA |
George Garcia | University of Michigan, USA |
Barry Gold | University of Pittsburgh, USA |
Steven V. Ley | University of Cambridge, UK |
María Luz López Rodríguez | Complutense University of Madrid, Spain |
Vânia Moreira | University of Helsinki, Finland |
Rui Moreira | University of Lisbon, Portugal |
Shinya Oishi | Kyoto University, Japan |
Christian A. Olsen | University of Copenhagen, Denmark |
Marco Radi | University of Parma, Italy |
Yu Rao | Tsinghua University, China |
Maria Santos | University of Lisbon, Portugal |
Peter Spielmann | University of Kentucky, USA |
Takanori Suzuki | Kyoto Prefectural University of Medicine, Japan |
Joseph Sweeney | University of Huddersfield, UK |
Katsunori Tanaka | RIKEN, Japan |
Henk Timmerman | Vrije Universiteit Amsterdam, Netherlands |
Gemma Triola | Instituto de Química Avanzada de Cataluña – CSIC, Spain |
Asier Unciti-Broceta | University of Edinburgh, UK |
Pieter van der Veken | University of Antwerp, Belgium |
Steven Van Lanen | University of Kentucky, USA |
Xiaojian Wang | Institute of Materia Medica, CAMS, China |
Kenji Watanabe | University of Shizuoka, Japan |
Young research associates/postdoctoral fellows/graduate students | |
Federico Falchi | Istituto Italiano di Tecnologia, Italy |
Maria Rosaria Ferraro | University of Bologna, Italy |
Marina Fosso | University of Kentucky, USA |
Keith Green | University of Kentucky, USA |
Matteo Masetti | University of Bologna, Italy |
Huy Ngo | University of Kentucky, USA |
And 20 anonymous responses |
Footnote |
† The last names of some of those from which parts of the text were inspired are written into parentheses (see Table 1 for details). We thank everyone who provided his/her opinion and apologize for not citing all contributors within the text. Below please find a list of all of those who contributed their answers to the question “What it medicinal chemistry?” that helped write this short opinion article (note: some of our responses came from anonymous sources). |
This journal is © The Royal Society of Chemistry 2017 |