Abstract
It is increasingly clear that academic high-throughput screening (HTS) and virtual HTS triage suffers from a lack of scientists trained in the art and science of early drug discovery chemistry. Many recent publications report the discovery of compounds by screening that are most likely artifacts or promiscuous bioactive compounds, and these results are not placed into the context of previous studies. For HTS to be most successful, it is our contention that there must exist an early partnership between biologists and medicinal chemists. Their combined skill sets are necessary to design robust assays and efficient workflows that will weed out assay artifacts, false positives, promiscuous bioactive compounds and intractable screening hits, efforts that ultimately give projects a better chance at identifying truly useful chemical matter. Expertise in medicinal chemistry, cheminformatics and purification sciences (analytical chemistry) can enhance the post-HTS triage process by quickly removing these problematic chemotypes from consideration, while simultaneously prioritizing the more promising chemical matter for follow-up testing. It is only when biologists and chemists collaborate effectively that HTS can manifest its full promise.
Acknowledgements
JL Dahlin gratefully acknowledges the Mayo Clinic librarians for assistance in obtaining scientific literature and Dr Zhiguo Zhang of the Mayo Clinic for mentorship. MA Walters acknowledges all members of the former Lead Discovery Group (Ann Arbor; MI, USA). JL Dahlin and MA Walters acknowledge the members of the LaPD and ITDD for helpful discussions.
Disclaimer
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The opinions or assertions contained herein belong to the authors and are not necessarily the official views of the funders. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Financial & competing interests disclosure
This work was supported by the Minnesota Partnership for Biotechnology and Medical Genomics (#73-01), the NIH, the Mayo Foundation for Medical Education and Research and the Minnesota Supercomputing Institute. JL Dahlin was supported by the NIH Medical Scientist Training Program at the Mayo Clinic (T32 GM065841), an NIH predoctoral fellowship (F30 DK092026-01), a Pharmaceutical Research and Manufacturers of America Foundation predoctoral pharmacology/toxicology fellowship and the Mayo Foundation. Some of the research reported in this publication was supported bythe National Institute of Neurological Disorders and Stroke (NINDS) of the NIH under award number ARRA-NS045667-07S1. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.