Collaborative drug discovery: an update on the progress of such initiatives

The National Institute of Health Molecular Libraries Program and the National Center for Advancing Translational Sciences

The National Institute of Health Molecular Libraries Program (MLP) was one of the earliest (established in 2004) and largest state-funded initiatives that intended to implement early stage drug discovery. There was a particular focus upon assay development and the screening of such assays against small molecule libraries, in a manner similar to that implemented within the pharmaceutical industry¹. The initial plan of the MLP was to build a library of compounds and establish screening centres outside the pharmaceutical industry where many of these activities historically took place. The capital and resources required were significant and the vision was to perform two very different kinds of screens, namely functional screening where compounds would be evaluated against known targets as well as phenotypic screening where unbiased testing of compounds would take place in cell based assays without knowing their targets. This was a reasonable strategy as both types of approaches complement one another and a recent publication has highlighted the value of the more risky phenotypic screening approach².

A notable effect of the MLP was to embed drug discovery within academia. The most significant findings of the MLP have been published in high ranking journals and compounds that have progressed in the drug discovery value chain, notably the publication of a chemically tractable new mechanism for controlling the cytokine storms that prove so deadly in pandemic influenza³, description of a novel, tractable mechanism for the treatment of type 2 diabetes⁴, elucidation of a high-resolution crystal structure of the S1P1 receptor⁵ and production of over 250 probes (small molecules that can be used as research tools to interrogate previously inaccessible targets, if not as drugs themselves), directly responsibility for at least 342 scientific publications⁶. The screening results have been deposited in a publicly available database, PubChem, which is accessed by a large number of users and is a valuable resource of assays and screens and associated data⁷. A side-effect of the MLP is that most major universities now have internal drug discovery centres that attempt to translate basic research findings into the drug discovery value chain⁸. Despite these successes, a notable downside of the MLP is that the attrition of projects was significant in terms of delivering compounds that would be considered to meet the criteria for progression within the pharmaceutical industry⁹. The outputs of the MLP are valuable and publically available and include, full reports of the probes that have been delivered¹⁰, detailed reports of projects e.g. caspase-1¹¹ and 12-lipoxygenase¹² and publically available peer-reviewed publications e.g. assays to search for inhibitors of Schistosoma mansoni thioredoxin glutathione reductase^13-15.