Fragment-to-Lead Medicinal Chemistry Publications in 2018.

This Perspective, the fourth in an annual series, summarizes fragment-to-lead (F2L) success stories published during 2018. Topics such as target class, screening methods, physicochemical properties, and ligand efficiency are discussed for the 2018 examples as well as for the combined 111 F2L examples covering 2015-2018. While the overall properties of fragments and leads have remained constant, a number of new trends are noted, for example, broadening of target class coverage and application of FBDD to covalent inhibitors. Moreover, several studies make use of fragment hits that were previously described in the literature, illustrating that fragments are versatile starting points that can be optimized to structurally diverse leads. By focusing on success stories, the hope is that this Perspective will identify and inform best practices in fragment-based drug discovery.

Fragment-to-Lead Medicinal Chemistry Publications in 2017.

This Miniperspective is the third in a series reviewing fragment-to-lead publications from a given year. Following our reviews for 2015 and 2016, this Miniperspective provides tabulated summaries of relevant articles published in 2017 along with some general observations. In addition, we discuss insights obtained from analysis of the combined data set of 85 examples from all three years of publications.

Efficient exploration of chemical space by fragment-based screening.

Screening methods seek to sample a vast chemical space in order to identify starting points for further chemical optimisation. Fragment based drug discovery exploits the superior sampling of chemical space that can be achieved when the molecular weight is restricted. Here we show that commercially available fragment space is still relatively poorly sampled and argue for highly sensitive screening methods to allow the detection of smaller fragments. We analyse the properties of our fragment library versus the properties of X-ray hits derived from the library. We particularly consider properties related to the degree of planarity of the fragments.

Assessing the lipophilicity of fragments and early hits.

A key challenge in many drug discovery programs is to accurately assess the potential value of screening hits. This is particularly true in fragment-based drug design (FBDD), where the hits often bind relatively weakly, but are correspondingly small. Ligand efficiency (LE) considers both the potency and the size of the molecule, and enables us to estimate whether or not an initial hit is likely to be optimisable to a potent, druglike lead. While size is a key property that needs to be controlled in a small molecule drug, there are a number of additional properties that should also be considered. Lipophilicity is amongst the most important of these additional properties, and here we present a new efficiency index (LLE(AT)) that combines lipophilicity, size and potency. The index is intuitively defined, and has been designed to have the same target value and dynamic range as LE, making it easily interpretable by medicinal chemists. Monitoring both LE and LLE(AT) should help both in the selection of more promising fragment hits, and controlling molecular weight and lipophilicity during optimisation.

Protein-ligand docking against non-native protein conformers.

In the validation of protein-ligand docking protocols, performance is mostly measured against native protein conformers, i.e. each ligand is docked into the protein conformation from the structure that contained that ligand. In real-life applications, however, ligands are docked against non-native conformations of the protein, i.e. the apo structure or a structure of a different protein-ligand complex. Here, we have constructed an extensive test set for assessing docking performance against non-native protein conformations. This new test set is built on the Astex Diverse Set (which we recently constructed for assessing native docking performance) and contains 1112 non-native structures for 65 drug targets. Using the protein-ligand docking program GOLD, the Astex Diverse Set and the new Astex Non-native Set, we established that, whereas docking performance (top-ranked solution within 2 A rmsd of the experimental binding mode) is approximately 80% for native docking, this drops to 61% for non-native docking. A similar drop-off is observed for sampling performance (any solution within 2 A): 91% for native docking vs 72% for non-native docking. No significant differences were observed between docking performance against apo and nonapo structures. We found that, whereas small variations in protein conformation are generally tolerated by our rigid docking protocol, larger protein movements result in a catastrophic drop-off in performance. Some docking performance and nearly all sampling performance can be recovered by considering dockings produced against a small number of non-native structures simultaneously. Docking against non-native structures of complexes containing ligands that are similar to the docked ligand also significantly improves both docking performance and sampling performance.