Malonate-based inhibitors of mammalian serine racemase: Kinetic characterization and structure-based computational study

Cyclopropane derivatives as potential human serine racemase inhibitors: unveiling novel insights into a difficult target

“…We repeated our docking experiment in its presence, and no productive poses for compound 5 were observed. As also pointed out by Vorlová et al 25 , the active site of SR X-ray crystal structures is indeed filled with ordered water molecules, suggesting a possible structural role for at least some of them. For example, W355 (3L6B numbering scheme) is present in all the crystal structures ( Table 2, W8) and it can be speculated having an important role in the stabilization of the phosphate group of PLP cofactor.…”

“…This almost complete lack of agreement between docking and experimental results deserved more investigation for a better exploitation of the available crystal structures of SR on route towards new potent inhibitors. In this respect, we drew inspiration from the work by Vorlová et al 25 and looked for the presence of water molecules in the crystal structures of SR which were not considered in the first docking experiments. In particular, in their work, they were quite successful in discerning qualitatively between good and weak binders.…”

“…Therefore, docking experiments were repeated using 3L6B crystal structure with structural water molecules W372, W373, and W403 explicitly considered, applying the same docking settings as in the studies by Vorlová et al 25 . Unfortunately, the results did not help us to finally have a full understanding of the situation.…”

“…For all the three software and for all the enzyme conformations used, the binding site grid box was centred on the centroid of the following residues: PLP, Ser84, Ser85, Arg135, Asn154, Ser242, and Thr285 (3L6B numbering). For the docking studies using 3L6B retaining the conserved water molecules, we applied the same protocol reported by Vorlová et al, with the grid centred on malonate 25 .…”

“…Harty et al 26 . designed substrate analogues as potential inhibitors, Vorlova et al 25 synthesized a series of malonate analogues, and Mori et al 24 identified novel potential inhibitors of SR by in silico ligand-based screening. All the compounds reported in these works exhibit very low inhibitory potencies, with inhibition constants in the high micromolar to millimolar range, with the only exception of 2,2-dichloromalonate, characterized by a K i of 57 lM (Figure 1 Inspired by SR inhibitors based on the structure of malonate 23 , we investigated the possibility of developing a new series of potential SR inhibitors based on the cyclopropane scaffold.…”