Abstract
Alzheimer’s disease (AD) is a multi-factorial neurodegenerative disease that affects millions of elderly people worldwide. Due to its massive occurrence and severity, there is continuing and compelling need for the development of novel and effective drugs for improved treatment of AD. Since AD is characterized by the deficiency in cholinergic neurotransmission, acetyl cholinesterase (AChE) has been considered as a promising drug target. Herein we triggered our effort to design novel and potential inhibitors of AChE using a set of 24 flavonoid compounds having inhibitory activity against AChE. We carried out 3D-QSAR-based and pharmacophore-based identification of novel natural lead candidates. The 3D-QSAR model obtained using partial least square regression showed satisfactory parametric values (r 2 = 0.8227, q 2 = 0.6833 and pred-r 2 = 0.7893). Amongst total 14 pharmacophore hypothesis generated the one possessing following five features: one hydrogen bond acceptor, two hydrophobic regions and two aromatic rings, was considered to be the best pharmacophore hypothesis. Above-described robust and validated 3D-QSAR and pharmacophore models were used for carrying out prospective generic prediction and virtual screening on large natural compound libraries. The screened molecules from both the approaches were subjected for further docking analysis to reveal the binding modes of actions of these ligands. All the ligands were found to bind with both catalytic and anionic subsite of AChE. The molecular insights obtained from this study will be of high value for design and development of novel drugs for AD, possessing improved binding properties and low toxicity to human.
Similar content being viewed by others
References
Afantitis A, Melagraki G, Sarimveis H, Igglessi-Markopoulou O, Kollias G (2009) A novel QSAR model for predicting the inhibition of CXCR3 receptor by 4-N-aryl-[1,4] diazepane ureas. Eur J Med Chem 44:877–884
Agrawal R, Jain P, Dikshit SN (2012) Ligand-based pharmacophore detection, screening of potential gliptins and docking studies to get effective antidiabetic agents. Comb Chem High Throughput Screen 15:849–876
Bartus RT, Dean RL, Beer B, Lippa AS (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217:408–414
Berriman J (2003) Tau filaments from human brain and from in vitro assembly of recombinant protein show cross-structure. Proc Natl Acad Sci USA 100:9034–9038
Bhole RP, Borkar DD, Bhusari KP, Patil PA (2012) Design and synthesis of p-hydroxybenzohydrazide derivatives for their antimycobacterial activity. J Korean Chem Soc 56:236–245
Brufani M, Castellano C, Marta M, Murroni F, Oliverio A, Pagella PG, Pavone F, Pomponi M, Rugarli PL (1988) From physostigmine derivatives as new inhibitors of cholinesterase. In: Giacobini E, Becker RE (eds) Current research in Alzheimer therapy. Taylor & Francis, p 10
Camps P, Formosa X, Galdeano C, Gomez T, Munoz-Torrero D, Scarpellini M, Viayna E, Badia A, Clos MV, Camins A et al (2008) Novel donepezil-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation. J Med Chem 51:3588–3598
Cramer RD, Patterson DE, Bunce JD (1988) Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. J Am Chem Soc 110:5959–5967
Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK et al (2004) Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 47:1739–1749
Golbraikh A, Tropsha A (2002) Beware of q2! J Mol Graph Model 20:269–276
He XC, Feng S, Wang ZF, Shi Y, Zheng S, Xia Y, Jiang H, Tang XC, Bai D (2007) Study on dual-site inhibitors of acetylcholinesterase: highly potent derivatives of bis- and bifunctional huperzine B. Bioorg Med Chem 15:1394–1408
Inestrosa NC, Dinamarca MC, Alvarez A (2008) Amyloid–cholinesterase interactions. Implications for Alzheimer’s disease. FEBS J 275:625–632
Irwin JJ, Shoichet BK (2005) ZINC–a free database of commercially available compounds for virtual screening. J Chem Inf Model 45:177–182
Jung M, Park M (2007) Acetylcholinesterase inhibition by flavonoids from Agrimonia pilosa. Molecules 12:2130–2139
Kim H, Park BS, Lee KG, Choi CY, Jang SS, Kim YH, Lee SE (2005) Effects of naturally occurring compounds on fibril formation and oxidative stress of beta-amyloid. J Agric Food Chem 53:8537–8541
Kryger G, Silman I, Sussman JL (1999) Structure of acetylcholinesterase complexed with E2020 (Aricept): implications for the design of new anti-Alzheimer drugs. Structure 7:297–307
Lahiri DK, Farlow MR, Greig NH, Sambamurti K (2002) Current drug targets for Alzheimer’s disease treatment. Drug Dev Res 56:267–281
Leonetti F, Catto M, Nicolotti O, Pisani L, Cappa A, Stefanachi A, Carotti A (2008) Homo- and hetero-bivalent edrophonium-like ammonium salts as highly potent, dual binding site AChE inhibitors. Bioorg Med Chem 16:7450–7456
Mathuranath PS, George A, Ranjith N, Justus S, Kumar MS, Menon R, Sarma PS, Verghese J (2012) Incidence of Alzheimer’s disease in India: a 10 years follow-up study. Neurol India 60:625–630
Nayyar A, Monga V, Malde A, Coutinho E, Jain R (2007) Synthesis, anti-tuberculosis activity, and 3D-QSAR study of 4-(adamantan-1-yl)-2-substituted quinolines. Bioorg Med Chem 15:626–640
Neve RL, McPhie DL, Chen Y (2000) Alzheimer’s disease: a dysfunction of the amyloid precursor protein(1). Brain Res 886:54–66
Nowaczyk A, Kulig K (2012) QSAR studies on a number of pyrrolidin-2-one antiarrhythmic arylpiperazinyls. Med Chem Res 21:373–381
Perry EK, Perry RH, Gibson PH, Blessed G, Tomlinson BE (1977) A cholinergic connection between normal aging and senile dementia in the human hippocampus. Neurosci Lett 6:85–89
Piazzi L, Rampa A, Bisi A, Gobbi S, Belluti F, Cavalli A, Bartolini M, Andrisano V, Valenti P, Recanatini M (2003) 3-(4-[[Benzyl(methyl)amino]methyl]phenyl)-6,7-dimethoxy-2H-2-chromenone (AP2238) inhibits both acetylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation: a dual function lead for Alzheimer’s disease therapy. J Med Chem 46:2279–2282
Querfurth HW, Laferla FM (2010) Alzheimer’s Disease REPLY. N Engl J Med 362:1844–1845
Sahu NK, Shahi S, Sharma MC, Kohli DV (2011) QSAR studies on imidazopyridazine derivatives as PfPK7 inhibitors. Mol Simul 37:752–765
Schrodinger (2009). Schrodinger suite. LLC, New York, NY
Selkoe DJ (1999) Translating cell biology into therapeutic advances in Alzheimer’s disease. Nature 399:A23–A31
Sheng R, Lin X, Zhang J, Chol KS, Huang WH, Yang B, He QJ, Hu YZ (2009) Design, synthesis and evaluation of flavonoid derivatives as potent AChE inhibitors. Bioorg Med Chem 17:6692–6698
Słowiński T, Stefanowicz J, Wróbel MZ, Herold F, Mazurek A, Pluciński F, Mazurek AP, Wolska I (2013) Model structure–activity relationship studies of potential tropane 5HT1A, 5HT2A, and D2 receptor ligands. Med Chem Res 22:3148–3153
Smith DA (2009) Treatment of Alzheimer’s disease in the long-term-care setting. Am J Health Syst Pharm 66:899–907
Verma J, Khedkar VM, Coutinho EC (2010) 3D-QSAR in drug design: a review. Curr Top Med Chem 10:95–115
VLifeMDS: Molecular Design Suite (2010). Pune, India, VLife Sciences Technologies Pvt. Ltd
Wallace AC, Laskowski RA, Thornton JM (1995) LIGPLOT: a program to generate schematic diagrams of protein–ligand interactions. Protein Eng 8:127–134
Acknowledgments
AG is thankful to Jawaharlal Nehru University for usage of all computational facilities. AG is grateful to University Grants Commission, India for the Faculty Recharge position.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Goyal, M., Grover, S., Dhanjal, J.K. et al. Molecular modelling studies on flavonoid derivatives as dual site inhibitors of human acetyl cholinesterase using 3D-QSAR, pharmacophore and high throughput screening approaches. Med Chem Res 23, 2122–2132 (2014). https://doi.org/10.1007/s00044-013-0810-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00044-013-0810-2