Note: this is more a pamphlet than an actual project, I am afraid that there there is no obvious solution to the problem; it is about science against belief and modern witch doctors…
Among the worrisome developments of academic research in medicinal chemistry is the recurrent recourse to assaying frequent hitters to justify the amount of money spent on a given screening program. This, in combination with the many computer-based “rational” drug design approaches which are also producing nothing but frequent hitters presented as “rationally” discovered, is essentially killing true medicinal chemistry efforts. The recent epidemic has brought this problem to an unprecedented level as even the journals, with the highest impact factor and – let’s hope – a decent culture in the matter, actually allowed the publication of completely useless results. And a similar phenomenon is seen in too many recent patents.
Today, the lack of long-term academic research in MedChem (and plausibly industry) is visible in the lack of available (and pertinent) chemical libraries as well as the rise of repurposing approaches in which drugs, or almost successful drugs, are assayed for other biological effects. Concerning the first issue, vendors are of course existing but how long will it take to exhaust the potential of a given chemical library (hopefully not spiked with frequent hitters)? Still on this subject, the large databases listing the many chemicals existing got quickly dubbed the “this is not commercially available” bases since less and less chemists are available or willing to undertake the (re)synthesis of compounds selected out of computer-based scrying strategies. Concerning the second issue, drug side effects, beneficial or not, are a reality but believing that finding an interesting in vitro phenomenon should immediately lead to a clinical trial is at the least irresponsible or down right criminal. Side effects are not the main effects of a given drug and abandoning any though about undertaking a thorough structure-activity relationship studies to improve the former and minimize the latter is only illustrating the lack of medicinal chemistry expertise in the hospitals.
The unfortunate truth is that assaying frequent hitters and thus leading to useless reports describing their potential usefulness has reached such a critical level that a lot of rather scarce financial resources, along with the grant selection committees, are devoted to it. The main reason? There is no limit to the amount of publications possible; a single biological target can lead to hundreds of papers describing the effect of these frequent hitters; no referees will object (they do the same). Take for instance the forever lasting subject of reactive organic species which is probably one of the more visible tips of the iceberg. Moreover, no editor is willing to consider that there is a real problem; they also have a “publish or perish” quandary when so many prolific authors, thus endowed with plenty of grants and great h index, will submit such useless work.
Time to do something! Otherwise we will all have a choice between curcumin/quercetin-based herbal tea (as cure-all quackeries aka traditional medicine and let’s not mention hydroxychloroquine, Pangolin scale as well as Bat sauté) or extremely expensive biologics and no more real drug.
Thank you for reading.
Recent and very relevant publications on the COVID-19 issue:
Muratov, E. N.; Amaro, R.; Andrade, C. H.; Brown, N.; Ekins, S.; Fourches, D.; Isayev, O.; Kozakov, D.; Medina-Franco, J. L.; Merz, K. M.; Oprea, T.; Poroikov, V.; Schneider, G.; Todd, M.; Varnek, A.; Winkler, D. A.; Zakharov, A. V.; Cherkasov, A.; Tropsha, A. A critical overview of computational approaches employed for COVID-19 drug discovery. Chem. Soc. Rev. 2021, doi: 10.1039/d0cs01065k.
Sauvat, A.; Ciccosanti, F.; Colavita, F.; Di, R., M.; Castilletti, C.; Capobianchi, M. R.; Kepp, O.; Zitvogel, L.; Fimia, G. M.; Piacentini, M.; Kroemer, G. On-target versus off-target effects of drugs inhibiting the replication of SARS-CoV-2. Cell Death Dis. 2020, 11, 656.
Tummino, T. A.; Rezelj, V. V.; Fischer, B.; Fischer, A.; O’Meara, M. J.; Monel, B.; Vallet, T.; White, K. M.; Zhang, Z.; Alon, A.; Schadt, H.; O’Donnell, H. R.; Lyu, J.; Rosales, R.; McGovern, B. L.; Rathnasinghe, R.; Jangra, S.; Schotsaert, M.; Galarneau, J. R.; Krogan, N. J.; Urban, L.; Shokat, K. M.; Kruse, A.; García-Sastre, A.; Schwartz, O.; Moretti, F.; Vignuzzi, M.; Pognan, F.; Shoichet, B. K. Drug-induced phospholipidosis confounds drug repurposing for SARS-CoV-2. Science 2021, 373, 541-547.
Boerner, L. K. The antivirals that weren’t: drug repurposing for COVID-19 produced misleading results. C&En 2021, 99, (25), 7.
Bellera, C. L.; Llanos, M.; Gantner, M. E.; Rodriguez, S.; Gavernet, L.; Comini, M.; Talevi, A. Can drug repurposing strategies be the solution to the COVID-19 crisis? Expert Opin. Drug Dis. 2020, doi: 10.1080/17460441.2021.1863943.