Expanding medicinal chemistry space

Stapled peptide design: principles and roles of computation

“…High-throughput approaches for lead discovery have met with limited success when applied to PPIs [2]. This is not surprising, given that the chemical make-up of the small molecules that comprise high-throughput screening libraries is biased towards organic molecules that bind to the deeper pockets found in traditional protein targets, such as enzymes and Gprotein-coupled receptors [3]. Nevertheless, there have been several recent successes in targeting PPIs with small molecules [4].…”

Yeast Synthetic Biology Platform Generates Novel Chemical Structures as Scaffolds for Drug Discovery

“…Nevertheless, many compounds in these corporate collections still lack structural diversity and possess a relatively high lipophilicity and poor thermodynamic solubility. 1,2,5−7 …”

Discovery, Development, and Regulation of Natural Products

“…The 207 human targets described for small-molecule drugs correspond to only about 1% of the human genome and half of all drugs target only four protein classes [41]. So called 'undruggable' targets, such as protein-protein interactions and phosphatases, still await the identification of lead structures with the required qualities for lead or development candidates [40]. Although the expectations in natural products for the future are still high, an analysis of the distinct biological network between the targets of natural products and disease genes revealed that natural products, as a group, may still not contain enough versatility to yield suitable treatments for all heritable human diseases [42].…”

“…The historic focus of the pharmaceutical industry on a relatively small set of 'druggable' targets has resulted in the exploration of a very narrow chemical space appropriate for these targets [40]. The 207 human targets described for small-molecule drugs correspond to only about 1% of the human genome and half of all drugs target only four protein classes [41].…”

“…Even though natural products may not have coevolved with human proteins, they have emerged in nature to interact with biomolecules [74]. Natural products interact with a wide variety of proteins and other biological targets, acting also as modulators of cellular processes when they inhibit the difficult to target protein-protein interactions [27,40].…”