Focusing on shared subpockets – new developments in fragment-based drug discovery

Abstract

Introduction: Protein–protein interactions (PPIs) are important targets for understanding fundamental biology and for the development of therapeutic agents. Based on different physicochemical properties, numerous pieces of software (e.g., POCKETQUERY, ANCHORQUERY and FTMap) have been reported to find pockets on protein surfaces and have applications in facilitating the design and discovery of small-molecular-weight compounds that bind to these pockets.

Areas covered: The authors discuss a pocket-centric method of analyzing PPI interfaces, which prioritize their pockets for small-molecule drug discovery and the importance of multicomponent reaction chemistry as starting points for undruggable targets. The authors also provide their perspectives on the field.

Expert opinion: Only the tight interplay of efficient computational methods capable of screening a large chemical space and fast synthetic chemistry will lead to progress in the rational design of PPI antagonists in the future. Early drug discovery platforms will also benefit from efficient rapid feedback loops from early clinical research back to molecular design and the medicinal chemistry bench.

Keywords:

• Anchor
• ANCHORQUERY
• chemical space
• multicomponent reaction
• pocket cluster
• POCKETQUERY
• protein–protein interactions
• virtual screening

Declaration of interest

The lead author’s laboratory is supported by Innovative Medicines Initiative (Grant agreement #115489), the National Institutes of Health (Grant No. 1R01GM097082-01), the Qatar National Research Foundation (NPRP 6-053-3-012) and the STW (Grant No. PN13547). E Abdelraheem is also supported by the Egyptian Embassy. A Dömling and C Camacho are cofounder of Carmolex Inc. 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.

Notes

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