Miles JA

References (5)

Title : Discovery of drug-like acetylcholinesterase inhibitors by rapid virtual screening of a 6.9 million compound database - Miles_2021_Chem.Biol.Drug.Des__
Author(s) : Miles JA , Ng JH , Sreenivas BY , Courageux C , Igert A , Dias J , McGeary RP , Brazzolotto X , Ross BP
Ref : Chemical Biology Drug Des , : , 2021
Abstract : Cholinesterase inhibitors remain the mainstay of Alzheimer's disease treatment, and the search for new inhibitors with better efficacy and side effect profiles is ongoing. Virtual screening (VS) is a powerful technique for searching large compound databases for potential hits. This study used a sequential VS workflow combining ligand-based VS, molecular docking and physicochemical filtering to screen for CNS drug-like acetylcholinesterase inhibitors (AChEIs) amongst the 6.9 million compounds of the CoCoCo database. Eleven in silico hits were initially selected, resulting in the discovery of an AChEI with a K(i) of 3.2 microM. In vitro kinetics and in silico molecular dynamics experiments informed the selection of an additional seven analogues. This led to the discovery of two further AChEIs, with K(i) values of 2.9 microM and 0.65 microM. All three compounds exhibited reversible, mixed inhibition of AChE. Importantly, the in silico physicochemical filter facilitated the discovery of CNS drug-like compounds, such that all three inhibitors displayed high in vitro blood-brain barrier model permeability.
ESTHER : Miles_2021_Chem.Biol.Drug.Des__
PubMedSearch : Miles_2021_Chem.Biol.Drug.Des__
PubMedID: 33455074

Title : Recent Advances in Virtual Screening for Cholinesterase Inhibitors - Miles_2021_ACS.Chem.Neurosci_12_30
Author(s) : Miles JA , Ross BP
Ref : ACS Chem Neurosci , 12 :30 , 2021
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.
ESTHER : Miles_2021_ACS.Chem.Neurosci_12_30
PubMedSearch : Miles_2021_ACS.Chem.Neurosci_12_30
PubMedID: 33350300

Title : Rapid discovery of a selective butyrylcholinesterase inhibitor using structure-based virtual screening - Miles_2020_Bioorg.Med.Chem.Lett__127609
Author(s) : Miles JA , Kapure JS , Singh Deora G , Courageux C , Igert A , Dias J , McGeary RP , Brazzolotto X , Ross BP
Ref : Bioorganic & Medicinal Chemistry Lett , :127609 , 2020
Abstract : Acetylcholinesterase inhibitors are the mainstay of Alzheimer's disease treatments, despite only short-term symptomatic benefits and severe side effects. Selective butyrylcholinesterase inhibitors (BuChEIs) may be more effective treatments in late-stage Alzheimer's disease with fewer side effects. Virtual screening is a powerful tool for identifying potential inhibitors in large digital compound databases. This study used structure-based virtual screening combined with physicochemical filtering to screen two the InterBioScreen and Maybridge databases for novel selective BuChEIs. The workflow rapidly identified 22 potential hits in silico, resulting in the discovery of a human BuChEI with low-micromolar potency in vitro (IC(50) 2.4 muM) and high selectivity for butyrylcholinesterase over acetylcholinesterase. The compound was a rapidly reversible BuChEI with mixed-model in vitro inhibition kinetics. The binding interactions were investigated using in silico molecular dynamics, and by developing structure-activity relationships using nine analogues. The compound also displayed high permeability in an in vitro model of the blood-brain barrier.
ESTHER : Miles_2020_Bioorg.Med.Chem.Lett__127609
PubMedSearch : Miles_2020_Bioorg.Med.Chem.Lett__127609
PubMedID: 33039562

Title : Rivastigmine and metabolite analogues with putative Alzheimer's disease-modifying properties in a Caenorhabditis elegans model. - Dighe_2019_Commun.Chem_2_35
Author(s) : Dighe SN , De la Mora E , Chan S , Kantham S , McColl G , Miles JA , Veliyath SK , Sreenivas BY , Nassar ZD , Silman I , Sussman JL , Weik M , McGeary RP , Parat MO , Brazzolotto X , Ross BP
Ref : Communications chemistry , 2 :35 , 2019
Abstract : The development of polyphenols as drugs for Alzheimer's disease (AD) is thwarted by their meagre brain availability due to instability and poor druglikeness. Here we describe the successful development of stable, druglike polyphenolic analogues of the current AD drug rivastigmine, that have high apparent blood-brain barrier permeabilities and multifunctional properties for AD treatment. The compounds inhibit cholinesterases and amyloid beta (Abeta) fibrillation, protect against Abeta42-induced toxicity in vitro, and demonstrate efficacy in vivo in a transgenic Caenorhabditis elegans model expressing Abeta42, with potencies similar to rivastigmine and natural polyphenols. The results suggest that a tertiary amine substituent is amenable for developing water-soluble, membrane-permeable polyphenols, and its incorporation adjacent to a hydroxy group is favourable for intramolecular hydrogen bonding that facilitates membrane permeability. Carbamylation of one hydroxy group protects the polyphenols from degradation and mostly improves their membrane permeability. These design strategies may assist in the development of polyphenol-based drugs.
ESTHER : Dighe_2019_Commun.Chem_2_35
PubMedSearch : Dighe_2019_Commun.Chem_2_35
Gene_locus related to this paper: human-BCHE , torca-ACHE

Title : Effect of the Biphenyl Neolignan Honokiol on Abeta42-Induced Toxicity in Caenorhabditis elegans, Abeta42 Fibrillation, Cholinesterase Activity, DPPH Radicals, and Iron(II) Chelation - Kantham_2017_ACS.Chem.Neurosci_8_1901
Author(s) : Kantham S , Chan S , McColl G , Miles JA , Veliyath SK , Deora GS , Dighe SN , Khabbazi S , Parat MO , Ross BP
Ref : ACS Chem Neurosci , 8 :1901 , 2017
Abstract : The biphenyl neolignan honokiol is a neuroprotectant which has been proposed as a treatment for central nervous system disorders such as Alzheimer's disease (AD). The death of cholinergic neurons in AD is attributed to multiple factors, including accumulation and fibrillation of amyloid beta peptide (Abeta) within the brain; metal ion toxicity; and oxidative stress. In this study, we used a transgenic Caenorhabditis elegans model expressing full length Abeta42 as a convenient in vivo system for examining the effect of honokiol against Abeta-induced toxicity. Furthermore, honokiol was evaluated for its ability to inhibit Abeta42 oligomerization and fibrillation; inhibit acetylcholinesterase and butyrylcholinesterase; scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals; and chelate iron(II). Honokiol displayed activity similar to that of resveratrol and (-)-epigallocatechin gallate (EGCG) in delaying Abeta42-induced paralysis in C. elegans, and it exhibited moderate-to-weak ability to inhibit Abeta42 on-pathway aggregation, inhibit cholinesterases, scavenge DPPH radicals, and chelate iron(II). Moreover, honokiol was found to be chemically stable relative to EGCG, which was highly unstable. Together with its good drug-likeness and brain availability, these results suggest that honokiol may be amenable to drug development and that the synthesis of honokiol analogues to optimize these properties should be considered.
ESTHER : Kantham_2017_ACS.Chem.Neurosci_8_1901
PubMedSearch : Kantham_2017_ACS.Chem.Neurosci_8_1901
PubMedID: 28650631