Recent Advances in Virtual Screening for Cholinesterase Inhibitors

Abstract

Alzheimer’s disease (AD) is a significant health crisis, and current treatments provide only limited benefits to cognition at the cost of serious side effects. Recently, virtual screening techniques such as ligand-based virtual screening (LBVS) and structure-based virtual screening (SBVS) have emerged as powerful drug discovery tools for identifying potential ligands of a biological target from a large database of chemical structures. The cholinesterases are an AD target particularly well suited for drug discovery using virtual screening due to their well-characterized active sites and comprehensive understanding of the structure–activity relationships of existing inhibitors. Over the last 5 years (2015–2020), at least 15 studies have used virtual screening techniques to discover potent new cholinesterase inhibitors. Herein we review how LBVS and SBVS have been applied individually or in tandem to discover novel acetylcholinesterase and butyrylcholinesterase inhibitors for AD, and highlight the need to confirm in vitro activity of screening compounds.

Combination of Docking-Based and Pharmacophore-Based Virtual Screening Identifies Novel Agonists That Target the Urotensin Receptor

“…Pharmacophore-based VS is based on the assumption that a molecule with a similar structure (in terms of structure, pharmacophoric features, molecular fields, etc.) also exhibits similar behavior [35,36]. Compared with a previous report that the pharmacophores were derived from U-II [24], in this study, we used 18 structurally diverse molecules for pharmacophore generation, which may have more diverse pharmacophores, thereby increasing the sensitivity.…”

Gender Differences in Demographic and Pharmacological Factors in Patients Diagnosed with Late-Onset of Alzheimer’s Disease

“…Currently, the main therapy for AD ranging from mild to severe AD are the cholinesterase inhibitors (ChEIs) [ 30 , 31 ]. Positive cognitive and global symptomatic effects of ChEI therapy have been reported in a randomized clinical trial [ 32 ] and observational studies [ 33 , 34 , 35 ] for both EOAD and LOAD [ 5 ]. While LOAD has been reported to present more functional deficits and severities than the EOAD [ 36 ], possible differences in demographic and other pharmacological factors in patients treated with and without ChEIs, and how this might contribute to a gender difference in a cohort with exclusively LOAD is not fully understood.…”

Discovery of octahydropyrrolo [3,2‐b] pyridin derivative as a highly selective Type I inhibitor of FGFR3 over VEGFR2 by high‐throughput virtual screening

“…At present, the inhibitor of Type I that can selectively inhibit FGFR3 rather than VEGFR2 has only been reported experimentally, 4 while few computational studies were performed. In drug discovery, virtual screening by pharmacophore modeling and molecular docking in drug databases have been applied widely in identifying new drug candidates against the individual target 28 . Therefore, in this work, we mainly focused on the in‐silicon exploration of new scaffolds as selective inhibitors of FGFR3 over VEGFR2 with the following workflow (Figure 1): first, two generated and validated ligand‐based pharmacophore models were utilized to screen for the molecules from Drugbank and Asinex databases; next, two docking protocols are tried to dock the molecules against two targets that conform to the FGFR3 pharmacophore model but not fit that of VEGFR2; finally, the stabilities of obtained hit molecules binding with FGFR3 or VEGFR2 target were explored by molecular dynamics (MD) simulation as well as post‐MD analysis.…”