optimization phase. It can be difficult for PhD students to get engaged in such kind of optimization campaigns when their future career may depend on successful publication outcome of their thesis. Even for the PI it may be challenging to maintain resources and patience with an optimization program when the first high impact publication is out and the tedious fine‐tuning begins to optimize and eventually identify a preclinical candidate. The needed persistence requires access to a suitable infrastructure and required critical resources.
The in‐depth knowledge on how molecules are successfully optimized is not regularly taught at many universities. This expertise resides mainly in industrial research units. Lack of medicinal chemistry experience and key optimization parameters frequently leads to optimization campaigns solely focusing on inhibition potency and neglecting other important parameters like metabolic stability, permeability, or solubility.
These campaigns frequently deliver mediocre hits with micromolar potency and insufficient physicochemical properties, selectivity or ADME parameters. When pursuing licensing negotiations with business development units at universities and pharmaceutical ventures, different opinions on the maturity and valuation of the project may lead to significant disappointment on both sides. While the university side may be convinced that the identified micromolar asset is just ready to go into clinical development, the pharma side may consider the obtained structure as an advanced hit or early lead, at best. This will undoubtedly complicate definition of milestones and payment terms. Here both sides have to openly interact and educate each other.
However, the previously mentioned examples demonstrate the invaluable contributions of academic medicinal chemists to drug discovery. Many new approaches have already been brought to practice. A large number of academically developed drugs is listed in the WHO list of essential drugs. Also financially, it can pay off for a university to pursue drug discovery and try to convert ideas and concepts from fundamental science into clinical practice. The reduced internal research in big pharma calls for new models, and more scientists with experience in the pharmaceutical industry are starting groups in academic settings and importing the knowledge of the drug industry into universities. Specifically, the increased demand for translational research calls for professionalized drug research at academic centers and will make drug discovery a vital and indispensable discipline at academic institutions.
List of Abbreviations
| ADME | absorption, distribution, metabolism, and excretion |
| AIDS | acquired immune deficiency syndrome |
| AMP | adenosine monophosphate |
| BMS | Bristol Meyers Squibb |
| Ca | calcium |
| CCNSC | Cancer Chemotherapy National Service Center |
| CD20 | cluster of differentiation 20 |
| COVID‐19 | Coronavirus disease 2019 |
| CTCL | cutaneous T‐cell lymphoma |
| dL | deciliter |
| DMSO | dimethyl sulfoxide |
| DNA | deoxyribonucleic acid |
| FDA | Food and Drug Administration |
| FGF | Fibroblast Growth Factor |
| g | gram |
| GABA | γ‐aminobutyric acid |
| GAD | L-glutamic acid decarboxylase |
| GABA‐AT | γ‐aminobutyric acid aminotransferase |
| GBF | Gesellschaft für Biotechnologische Forschung |
| HDAC | histone deacetylase |
| HIV | human immunodeficiency virus |
| iBu | isobutyl |
| IC50 | half maximal inhibitory concentration |
| iPr | isopropyl |
| kg | kilogram |
| K i | dissociation constant of an inhibitor |
| L | liter |
| MELC | murine erythroleukemia cells |
| mg | milligram |
| mL | milliliter |
| mmol | millimol |
| NCE | new chemical entities |
| NCI | National Cancer Institute |
| N‐Lost | nitrogen lost |
| NMR | nuclear magnetic resonance |
| nPr | n‐Propyl |
| RA | rheumatoid arthritis |
| rac | racemic |
| SAHA | suberoylanilide hydroxamic acid |
| SAR | structure–activity relationship |
| sBu | sec‐butyl |
| S‐lost | sulfur‐lost |
| USDA | US Department of Agriculture |
| WHO | World Health Organization |
| μg | microgram |
| μM | micromolar |
References
1 1 Iervolino, A. and Urquhart, L. (ed.) (2017). EvaluatePharma World Preview 2017, Outlook to 2022, 10th ed, 19.
2 2
