Ab-initio and conformational analysis of a potent vegfr-2 inhibitor: a case study on motesanib

Vascular endothelial growth factor receptor-2 [VEGFR-2]; a cell surface receptor for vascular endothelial growth factors, is a key pharmacological target involved in the cell proliferation/angiogenesis. It has been revealed that VEGFR-2 induces proliferation through activation of the extracellular signal-regulated kinases pathway. In this regard, targeting the VEGFR-2 has been considered as an efficient route to develop anti-tumor agents. Motesanib is a small-molecule antagonist of VEGFR-1, 2, and 3 [IC50s; 2 nM, 3 nM, 6 nM, respectively]. It is an experimental drug candidate undergoing clinical trials against some types of cancer. In the present study, Motesanib [AMG 706] was evaluated in terms of its binding energies with individual amino acids of VEGFR-2 active site [amino acid decomposition analysis]. For this purpose, functional B3LYP associated with split valence basis set using polarization functions [Def2-SVP] was used. Comparative Conformational analysis of the ligand in optimized and crystallographic states revealed that Motesanib does not necessarily bind to the VEGFR-2 active site in its minimum energy conformer

Fragment-based binding efficiency indices in bioactive molecular design: a computational approach to BACE-1 inhibitors

One of the most important targets in Alzheimer disease is Beta site amyloid precursor protein cleaving enzyme-1 [BACE-1]. It is a membrane associated protein and is one of the main enzymes responsible for amyloid beta [A beta] production. Up to now, a considerable number of peptidic and non-peptidic inhibitors of BACE-1 have been developed. Recently, small molecule BACE-1 inhibitors have attracted the attention of scientists, because peptidic inhibitors have many pharmacokinetic problems. In the present study, several small molecule BACE-1 inhibitors were extracted from Brookhaven Protein Databank [PDB] and subjected to dissection analysis to achieve constructing fragments. Atom type, hybridization, and bond order were considered for generated constitutional fragments [simplified structures]. AutoDock version 4.2 was applied to dock various chemical fragments into BACE-1 active site. The benefits of such studies have been well revealed in previous reports. On the basis of obtained binding affinities, fragment-based ligand efficiency [LE] indices were estimated. These theoretical binding efficiencies were applied to further elucidate the key structural features of BACE-1 inhibitors. Typical results of the study were elucidated and we suggested the ways these findings might be beneficial to guide rational bioactive molecular developments. Our study confirmed that the evaluation of ligand-receptor interactions in terms of ligand efficiency indices [binding energy per atom and pK[i] per MW] could be a helpful strategy in structure-based drug discovery [SBDD] strategies