Le hot spot guided optimization of an achbp fragment hit

Our constructed ligand efficiency (LE) hot spot surface was used as a guide for structure-based optimization of an AChBP fragment hit. This fragment hit was an analogue of a fragment found in the radioligand binding assay performed on Ls-AChBP, described in Chapter 4. The chemical space around this original fragment was explored by SAR-by-catalogue, thereby increasing its affinity and ligand efficiency. It appeared to be difficult to predict a binding mode for the fragment hits, for several equally scored binding modes were obtained. This is a know phenomenon in fragment-based drug discovery which can be contributed to the low affinities and few interaction points fragments usually have. We used the LE hot spot surface (Chapter 6) for binding mode ranking. The fragment was expanded in silico; the docking modes of several virtual analogues helped in constructing a model for growing directions. Three different growing/optimization cycles were taken. The optimized ligand 43 had a 220-times higher affinity with respect to the initial fragment hit, with a comparable molecular weight and thus improved