Novel Strategy for Three-Dimensional Fragment-Based Lead Discovery

Abstract

Fragment-based drug design (FBDD) is considered a promising approach in lead discovery. However, for a practical application of this approach, problems remain to be solved. Hence, a novel practical strategy for three-dimensional lead discovery is presented in this work. Diverse fragments with spatial positions and orientations retained in separately adjacent regions were generated by deconstructing well-aligned known inhibitors in the same target active site. These three-dimensional fragments retained their original binding modes in the process of new molecule construction by fragment linking and merging. Root-mean-square deviation (rmsd) values were used to evaluate the conformational changes of the component fragments in the final compounds and to identify the potential leads as the main criteria. Furthermore, the successful validation of our strategy is presented on the basis of two relevant tumor targets (CDK2 and c-Met), demonstrating the potential of our strategy to facilitate lead discovery against some drug targets.

Fragment virtual screening based on Bayesian categorization for discovering novel VEGFR-2 scaffolds

“…In this technique, those molecules were not cleaved when their atoms exceeded the maximum number allowed to break. Above all, ringconnecting bonds and hydrogen bonds were not allowed to be fragmented [23]. Pipeline Pilot 7.5 was also adopted for fragmentation of molecules through the Generate Recap Fragments protocol.…”

“…For example, to discover scaffolds that can bind in the hinge region or other important regions (e.g., DFG region) is one of the most frequently adopted methodologies in searching novel kinase inhibitors. Although our group has formerly constructed a novel strategy using a user-defined fragmentation framework for three-dimensional (3D) fragment-based lead discovery [23], only the ligands extracted from the Protein Data Bank (PDB) were employed to generate fragments and construct novel hits. Therefore, to expand the scaffold chemical space, more molecules are required to sample fragments.…”

Pharmacophore modeling and virtual screening studies to identify new c-Met inhibitors

“…Other parameters were kept as default. All compounds were prepared with the LigPre module and then flexibly docked into the binding site with the extra precision (XP) docking mode selected [11].…”

“…To date, there are few papers on pharmacophore studies of c-Met inhibitors [10,11]. Here, we reported a reliable pharmacophore model based on a series of known cMet inhibitors.…”

Spirooxindoles as novel 3D-fragment scaffolds: Synthesis and screening against CYP121 from M. tuberculosis

“…One approach to increasing the structural diversity of libraries has been to introduce sp 3 carbon centres onto the fragment scaffold, thereby increasing the 3D character. [4][5][6][7] However, the routes to these compounds are often challenging and require multiple step syntheses.…”