Integration of pharmacophore mapping and molecular docking in sequential virtual screening: towards the discovery of novel JAK2 inhibitors

Abstract

An integrated virtual screening protocol by combining molecular docking and pharmacophore mapping was established to identify novel inhibitors of JAK2 from a commercial compound database. Twelve novel and structurally diverse hits were selected and subjected to in vitro biological tests, and three compounds (A5, A6 and A9) with remarkable JAK2 inhibitory activity were identified. Then, the obtained structures were further used as the template for a subsequent similarity search, leading to the identification of another two promising compounds (B2 and B4). Selectivity profiles of JAK subtype and in vitro anti-cancer activity of the promising compounds were studied, revealing the promising compound B2 was of interest for further study because of its JAK2 selective profile, novelty of skeleton and significantly anti-proliferative effect against cancer cells. Finally, binding patterns of the compounds A5 and B2 were explored to provide a deeper insight for further structural optimization.

Evaluation of Artificial Intelligence in Participating Structure-Based Virtual Screening for Identifying Novel Interleukin-1 Receptor Associated Kinase-1 Inhibitors

“…As a continuation of our virtual screening work which identified new inhibitors targeting NIK, CHK1, Akt, etc. (18)(19)(20)(21)(22)(23)(24). In this study, we performed a traditional VS procedure to identify potential inhibitors of IRAK1.…”

ADME Profiling in Drug Discovery and a New Path Paved on Silica

“…Despite the criticism and overinterpretation of Lipinski and derived rules, the influence of physicochemical parameters on oral bioavailability and related parameters (as logP and aqueous solubility) is notable. Moreover, these rules are still being employed nowadays in virtual screening campaigns aiming to reduce the number of compounds from massively large available libraries (e.g., ZINC, which contains more than 750 millions of compounds) [40][41][42]. Furthermore, those initial steps instigate the generation of more complex models to predict not just oral bioavailability but other PK-related parameters as Caco-2 permeability, aqueous solubility, Drug Discovery and Development -New Advances and logP as indirectly related properties as well as other direct parameters as intestinal absorption, metabolism, clearance, etc.…”

Ligand-based pharmacophore model for the discovery of novel CXCR2 antagonists as anti-cancer metastatic agents

“…Although a bunch of CXCR2 antagonists have been identified, the anti-tumour metastasis effect of CXCR2 antagonists has not been considered in most cases. In fact, we also have demonstrated the application of pharmacophores in finding various targets inhibitors [ 15 – 18 ], which provide a reliable tool in drug design. In this study, eight promising scaffolds were identified for the CXCR2 antagonist with the new pharmacophore we built, among those scaffold F was selected for future optimization.…”