Design and Synthesis of 56 Shape Diverse 3-D Fragments

Fragment-based drug discovery is now widely adopted for lead generation in the pharmaceutical industry. However, fragment screening collections are often predominantly populated with flat, 2-D molecules. Herein, we describe a workflow for the design and synthesis of 56 3-D disubstituted pyrrolidine and piperidine fragments that occupy under-represented areas of fragment space (as demonstrated by a principal moments of inertia (PMI) analysis). A key, and unique, underpinning design feature of this fragment collection is that assessment of fragment shape and conformational diversity (by considering conformations up to 1.5 kcal mol -1 above the energy of the global minimum energy conformer) is carried out prior to synthesis and is also used to select targets for synthesis. The 3-D fragments were designed to contain suitable synthetic handles for future fragment elaboration. Finally, by comparing our 3-D fragments with six commercial libraries, it is clear that our collection has high three-dimensionality and shape diversity

How common are Earth-Moon planetary systems?

The Earth’s comparatively massive moon, formed via a giant impact on the proto-Earth, has played an important role in the development of life on our planet, both in the history and strength of the ocean tides and in stabilizing the chaotic spin of our planet. Here we show that massive moons orbiting terrestrial planets are not rare. A large set of simulations by Morishima et al. (Morishima, R., Stadel, J., Moore, B. [2010]. Icarus. 207, 517–535), where Earth-like planets in the habitable zone form, provides the raw simulation data for our study. We use limits on the collision parameters that may guarantee the formation of a circumplanetary disk after a protoplanet collision that could form a satellite and study the collision history and the long term evolution of the satellites qualitatively. In addition, we estimate and quantify the uncertainties in each step of our study. We find that giant impacts with the required energy and orbital parameters for producing a binary planetary system do occur with more than 1 in 12 terrestrial planets hosting a massive moon, with a low-end estimate of 1 in 45 and a high-end estimate of 1 in 4