Rapid discovery of a selective butyrylcholinesterase inhibitor using structure-based virtual screening

被引:8
作者
Miles, Jared A. [1 ]
Kapure, Jeevak S. [1 ]
Deora, Girdhar Singh [1 ,2 ]
Courageux, Charlotte [3 ]
Igert, Alexandre [3 ]
Dias, Jose [3 ]
McGeary, Ross P. [4 ]
Brazzolotto, Xavier [3 ]
Ross, Benjamin P. [1 ]
机构
[1] Univ Queensland, Sch Pharm, Brisbane, Qld 4072, Australia
[2] Monash Univ, Monash Inst Pharmaceut Sci, Parkville, Vic 3052, Australia
[3] Inst Rech Biomed Armees, Dept Toxicol & Risques Chim, F-91223 Bretigny Sur Orge, France
[4] Univ Queensland, Sch Chem & Mol Biosci, Brisbane, Qld 4072, Australia
关键词
Alzheimer's disease; Butyrylcholinesterase; Inhibitor; Virtual screening; CHOLINESTERASE-INHIBITORS; ALZHEIMERS-DISEASE; SENILE DEMENTIA; ACETYLCHOLINESTERASE;
D O I
10.1016/j.bmcl.2020.127609
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Acetylcholinesterase inhibitors are the mainstay of Alzheimer's disease treatments, despite having only shortterm 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 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 (IC50 2.4 mu M) 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.
引用
收藏
页数:5
相关论文
共 25 条
  • [1] [Anonymous], 2013, Policy brief for heads of government
  • [2] New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays
    Baell, Jonathan B.
    Holloway, Georgina A.
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2010, 53 (07) : 2719 - 2740
  • [3] Discovery, Biological Evaluation, and Crystal Structure of a Novel Nanomolar Selective Butyrylcholinesterase Inhibitor
    Brus, Boris
    Kosak, Urban
    Turk, Samo
    Pislar, Anja
    Coquelle, Nicolas
    Kos, Janko
    Stojan, Jure
    Colletier, Jacques-Philippe
    Gobec, Stanislav
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2014, 57 (19) : 8167 - 8179
  • [4] Pyrano[3,2-c]quinoline-6-Chlorotacrine Hybrids as a Novel Family of Acetylcholinesterase- and β-Amyloid-Directed Anti-Alzheimer Compounds
    Camps, Pelayo
    Formosa, Xavier
    Galdeano, Carles
    Munoz-Torrero, Diego
    Ramirez, Lorena
    Gomez, Elena
    Isambert, Nicolas
    Lavilla, Rodolfo
    Badia, Albert
    Victoria Clos, M.
    Bartolini, Manuela
    Mancini, Francesca
    Andrisano, Vincenza
    Arce, Mariana P.
    Isabel Rodriguez-Franco, M.
    Huertas, Oscar
    Dafni, Thomai
    Javier Luque, F.
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2009, 52 (17) : 5365 - 5379
  • [5] Structures of Human Acetylcholinesterase in Complex with Pharmacologically Important Ligands
    Cheung, Jonah
    Rudolph, Michael J.
    Burshteyn, Fiana
    Cassidy, Michael S.
    Gary, Ebony N.
    Love, James
    Franklin, Matthew C.
    Height, Jude J.
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (22) : 10282 - 10286
  • [6] Copeland RA, 2013, EVALUATION OF ENZYME INHIBITORS IN DRUG DISCOVERY: A GUIDE FOR MEDICINAL CHEMISTS AND PHARMACOLOGISTS, 2ND EDITION, P1, DOI 10.1002/9781118540398
  • [7] P-glycoprotein deficient mouse in situ blood-brain barrier permeability and its prediction using an in combo PAMPA model
    Dagenais, Claude
    Avdeef, Alex
    Tsinman, Oksana
    Dudley, Adam
    Beliveau, Richard
    [J]. EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, 2009, 38 (02) : 121 - 137
  • [8] Rivastigmine and metabolite analogues with putative Alzheimer's disease-modifying properties in a Caenorhabditis elegans model
    Dighe, Satish N.
    De la Mora, Eugenio
    Chan, Stephen
    Kantham, Srinivas
    McColl, Gawain
    Miles, Jared A.
    Veliyath, Suresh Kumar
    Sreenivas, B. Yogi
    Nassar, Zeyad D.
    Silman, Israel
    Sussman, Joel L.
    Weik, Martin
    McGeary, Ross P.
    Parat, Marie-Odile
    Brazzolotto, Xavier
    Ross, Benjamin P.
    [J]. COMMUNICATIONS CHEMISTRY, 2019, 2 (1)
  • [9] Discovery and Structure-Activity Relationships of a Highly Selective Butyrylcholinesterase Inhibitor by Structure-Based Virtual Screening
    Dighe, Satish N.
    Deora, Girdhar Singh
    De la Mora, Eugenio
    Nachon, Florian
    Chan, Stephen
    Parat, Marie-Odile
    Brazzolotto, Xavier
    Ross, Benjamin P.
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2016, 59 (16) : 7683 - 7689
  • [10] Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy
    Friesner, RA
    Banks, JL
    Murphy, RB
    Halgren, TA
    Klicic, JJ
    Mainz, DT
    Repasky, MP
    Knoll, EH
    Shelley, M
    Perry, JK
    Shaw, DE
    Francis, P
    Shenkin, PS
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (07) : 1739 - 1749