Abstract

Drug Discovery Efforts Mirror the Proverbial Hyper Cycle: What’s Next?

Rathnam Chaguturu, Founder and CEO/Senior Director, SRI International

The process of drug discovery has benefited in the past decade by the advent and rise of high-throughput screening (HTS), an early and vital step of screening small molecule libraries primarily through biochemical and cell-based assays. While the discovery of new therapeutic drug targets in the post-human-genome-sequencing era is at an all time high, the introduction of new molecular entities against therapeutic targets is at an all-time low. HTS gained popularity and prominence as a means to that end. Central to every HTS endeavor is the compound collection. Industry-style probe discovery has now gained unparalleled momentum in academia with the availability of vendor-supplied chemical libraries and ready access to institutional HTS laboratories. These library collections are designed and selected for drug-like properties and structural diversity, which is critical to identifying unique hits to screening targets. Millions of compounds are now commercially available. Both academia and pharma are engaged in screening large compound libraries, corporate databases, virtual compound collections and suppliers’ databases for lead drug candidates.
>Although the 11 million-plus compounds that comprise the vendor-supplied chemical libraries are designed with a biogenic bias, almost eighty percent of the core ring scaffolds present among the natural products are surprisingly absent in the commercially available molecules, and by extension, the screening libraries. While statistically defined chemical space is similar for natural products and marketed drugs, the combinatorially-derived chemical libraries do not share similar space. Compared to the natural products, the combinatorially-derived chemical libraries are almost devoid of chiral centers, low on oxygen atoms and rich in nitrogen - the key features that dictate target selectivity, specificity, and in-vivo metabolism. The wealth of chemical diversity that has evolved with biological diversity is underrepresented i