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Real-world evidence (RWE) is an emerging scientific discipline which is being increasingly utilised for decision making on prescription only medicines. However, there has been little focus to date on the application of RWE within the non-prescription sector. This paper reviews the existing and potential applications of RWE for non-prescription medicines, using the non-prescription medicine life-cycle as a framework for discussion. Relevant sources of real-world data (RWD) are reviewed and compared with those available for prescribed medicines. Existing life-cycle data gaps are identified where RWE is required or where use of RWE can complement data from randomised controlled trials (RCTs). Published RWE examples relating to non-prescription medicines are summarised, and potential relevant future sources of RWD discussed. Challenges and limitations to the use of RWE on non-prescription medicines are discussed, and recommendations made to promote optimal and appropriate use of RWE in this sector. Overall, RWE currently plays a key role in specific phases of the non-prescription medicine life-cycle, including reclassification and post-marketing safety surveillance. The increasing availability of patient-generated health data (PGHD) is likely to further increase the utilisation of RWE to aid decision making on non-prescription medicines.

Sec14-like phosphatidylinositol transfer proteins (PITPs) integrate diverse territories of intracellular lipid metabolism with stimulated phosphatidylinositol-4-phosphate production and are discriminating portals for interrogating phosphoinositide signaling. Yet, neither Sec14-like PITPs nor PITPs in general have been exploited as targets for chemical inhibition for such purposes. Herein, we validate what is to our knowledge the first small-molecule inhibitors (SMIs) of the yeast PITP Sec14. These SMIs are nitrophenyl(4-(2-methoxyphenyl)piperazin-1-yl)methanones (NPPMs) and are effective inhibitors in vitro and in vivo. We further establish that Sec14 is the sole essential NPPM target in yeast and that NPPMs exhibit exquisite targeting specificities for Sec14 (relative to related Sec14-like PITPs), propose a mechanism for how NPPMs exert their inhibitory effects and demonstrate that NPPMs exhibit exquisite pathway selectivity in inhibiting phosphoinositide signaling in cells. These data deliver proof of concept that PITP-directed SMIs offer new and generally applicable avenues for intervening with phosphoinositide signaling pathways with selectivities superior to those afforded by contemporary lipid kinase-directed strategies.

We investigated a series of sulfonamide boronic acids that resulted from the merging of two unrelated AmpC β-lactamase inhibitor series. The new boronic acids differed in the replacement of the canonical carboxamide, found in all penicillin and cephalosporin antibiotics, with a sulfonamide. Surprisingly, these sulfonamides had a highly distinct structure-activity relationship from the previously explored carboxamides, high ligand efficiencies (up to 0.91), and K(i) values down to 25 nM and up to 23 times better for smaller analogues. Conversely, K(i) values were 10-20 times worse for larger molecules than in the carboxamide congener series. X-ray crystal structures (1.6-1.8 Å) of AmpC with three of the new sulfonamides suggest that this altered structure-activity relationship results from the different geometry and polarity of the sulfonamide versus the carboxamide. The most potent inhibitor reversed β-lactamase-mediated resistance to third generation cephalosporins, lowering their minimum inhibitory concentrations up to 32-fold in cell culture.

Molecular docking has become a valuable technique for structure-based drug discovery, including fragment-based approaches. This review summarizes the latest development in screening technologies using fragment docking and scoring, including probing binding hot spots in silico , screening fragment databases and fragment-based docking of drug-like molecules. The challenges of sampling protein flexibility and improving scoring functions are also discussed. The continuing development of fragment-based docking will provide an effective approach to sample novel areas of chemical space for drug design.