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Application of fragment-based NMR screening, X-ray crystallography, structure-based design, and focused chemical library design to identify novel microM leads for the development of nM BACE-1 (beta-site APP cleaving enzyme 1) inhibitors.

Wang YS, Strickland C, Voigt JH, Kennedy ME, Beyer BM, Senior MM, Smith EM, Nechuta TL, Madison VS, Czarniecki M, McKittrick BA, Stamford AW, Parker EM, Hunter JC, Greenlee WJ, Wyss DF
J Med Chem 53 942-50 (2010)
Related entries: 3kmy, 3kn0

Cited: 42 times
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Abstract

Fragment-based NMR screening, X-ray crystallography, structure-based design, and focused chemical library design were used to identify novel inhibitors for BACE-1. A rapid optimization of an initial NMR hit was achieved by a combination of NMR and a functional assay, resulting in the identification of an isothiourea hit with a K(d) of 15 microM for BACE-1. NMR data and the crystal structure revealed that this hit makes H-bond interactions with the two catalytic aspartates, occupies the nonprime side region of the active site of BACE-1, and extends toward the S3 subpocket (S3sp). A focused NMR-based search for heterocyclic isothiourea isosteres resulted in several distinct classes of BACE-1 active site directed compounds with improved chemical stability and physicochemical properties. The strategy for optimization of the 2-aminopyridine lead series to potent inhibitors of BACE-1 was demonstrated. The structure-based design of a cyclic acylguanidine lead series and its optimization into nanomolar BACE-1 inhibitors are the subject of the companion paper

Reviews - 3kmx mentioned but not cited (1)

  1. Lessons from Hot Spot Analysis for Fragment-Based Drug Discovery. Hall DR, Kozakov D, Whitty A, Vajda S. Trends Pharmacol Sci 36 724-736 (2015)

Articles - 3kmx mentioned but not cited (4)

  1. Flavonoids lower Alzheimer's Aβ production via an NFκB dependent mechanism. Paris D, Mathura V, Ait-Ghezala G, Beaulieu-Abdelahad D, Patel N, Bachmeier C, Mullan M. Bioinformation 6 229-236 (2011)
  2. Fragment-based Binding Efficiency Indices in Bioactive Molecular Design: A Computational Approach to BACE-1 Inhibitors. Razzaghi-Asl N, Ebadi A, Edraki N, Shahabipour S, Miri R. Iran J Pharm Res 12 423-436 (2013)
  3. Dissimilar Ligands Bind in a Similar Fashion: A Guide to Ligand Binding-Mode Prediction with Application to CELPP Studies. Xu X, Zou X. Int J Mol Sci 22 12320 (2021)
  4. Partial Characterization of Two Cathepsin D Family Aspartic Peptidases of Clonorchis sinensis. Kang JM, Yoo WG, Lê HG, Thái TL, Hong SJ, Sohn WM, Na BK. Korean J Parasitol 57 671-680 (2019)


Reviews citing this publication (11)

  1. Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects. Vassar R, Kuhn PH, Haass C, Kennedy ME, Rajendran L, Wong PC, Lichtenthaler SF. J Neurochem 130 4-28 (2014)
  2. Structural biology in fragment-based drug design. Murray CW, Blundell TL. Curr Opin Struct Biol 20 497-507 (2010)
  3. NMR-based approaches for the identification and optimization of inhibitors of protein-protein interactions. Barile E, Pellecchia M. Chem Rev 114 4749-4763 (2014)
  4. Stepping closer to treating Alzheimer's disease patients with BACE1 inhibitor drugs. Yan R. Transl Neurodegener 5 13 (2016)
  5. High-Throughput Screening by Nuclear Magnetic Resonance (HTS by NMR) for the Identification of PPIs Antagonists. Wu B, Barile E, De SK, Wei J, Purves A, Pellecchia M. Curr Top Med Chem 15 2032-2042 (2015)
  6. Inhibitors of BACE for treating Alzheimer's disease: a fragment-based drug discovery story. Stamford A, Strickland C. Curr Opin Chem Biol 17 320-328 (2013)
  7. NMR-Fragment Based Virtual Screening: A Brief Overview. Singh M, Tam B, Akabayov B. Molecules 23 E233 (2018)
  8. Results of Beta Secretase-Inhibitor Clinical Trials Support Amyloid Precursor Protein-Independent Generation of Beta Amyloid in Sporadic Alzheimer's Disease. Volloch V, Rits S. Med Sci (Basel) 6 E45 (2018)
  9. Advances in the identification of β-secretase inhibitors. Hamada Y, Kiso Y. Expert Opin Drug Discov 8 709-731 (2013)
  10. Screening Strategies and Methods for Better Off-Target Liability Prediction and Identification of Small-Molecule Pharmaceuticals. Van Vleet TR, Liguori MJ, Lynch JJ, Rao M, Warder S. SLAS Discov 24 1-24 (2019)
  11. The β-secretase (BACE) inhibitor NB-360 in preclinical models: From amyloid-β reduction to downstream disease-relevant effects. Neumann U, Machauer R, Shimshek DR. Br J Pharmacol 176 3435-3446 (2019)

Articles citing this publication (26)

  1. Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor that Affords Robust CNS Aβ Reduction. Stamford AW, Scott JD, Li SW, Babu S, Tadesse D, Hunter R, Wu Y, Misiaszek J, Cumming JN, Gilbert EJ, Huang C, McKittrick BA, Hong L, Guo T, Zhu Z, Strickland C, Orth P, Voigt JH, Kennedy ME, Chen X, Kuvelkar R, Hodgson R, Hyde LA, Cox K, Favreau L, Parker EM, Greenlee WJ. ACS Med Chem Lett 3 897-902 (2012)
  2. Flexibility of the flap in the active site of BACE1 as revealed by crystal structures and molecular dynamics simulations. Xu Y, Li MJ, Greenblatt H, Chen W, Paz A, Dym O, Peleg Y, Chen T, Shen X, He J, Jiang H, Silman I, Sussman JL. Acta Crystallogr D Biol Crystallogr 68 13-25 (2012)
  3. From fragment screening to in vivo efficacy: optimization of a series of 2-aminoquinolines as potent inhibitors of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1). Cheng Y, Judd TC, Bartberger MD, Brown J, Chen K, Fremeau RT, Hickman D, Hitchcock SA, Jordan B, Li V, Lopez P, Louie SW, Luo Y, Michelsen K, Nixey T, Powers TS, Rattan C, Sickmier EA, St Jean DJ, Wahl RC, Wen PH, Wood S. J Med Chem 54 5836-5857 (2011)
  4. Application of consensus scoring and principal component analysis for virtual screening against β-secretase (BACE-1). Liu S, Fu R, Zhou LH, Chen SP. PLoS One 7 e38086 (2012)
  5. Sensitive and continuous screening of inhibitors of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) at single SPR chips. Yi X, Hao Y, Xia N, Wang J, Quintero M, Li D, Zhou F. Anal Chem 85 3660-3666 (2013)
  6. 19 F NMR-Based Fragment Screening for 14 Different Biologically Active RNAs and 10 DNA and Protein Counter-Screens. Binas O, de Jesus V, Landgraf T, Völklein AE, Martins J, Hymon D, Kaur Bains J, Berg H, Biedenbänder T, Fürtig B, Lakshmi Gande S, Niesteruk A, Oxenfarth A, Shahin Qureshi N, Schamber T, Schnieders R, Tröster A, Wacker A, Wirmer-Bartoschek J, Wirtz Martin MA, Stirnal E, Azzaoui K, Richter C, Sreeramulu S, José Blommers MJ, Schwalbe H. Chembiochem 22 423-433 (2021)
  7. Synergistic inhibitor binding to the papain-like protease of human SARS coronavirus: mechanistic and inhibitor design implications. Lee H, Cao S, Hevener KE, Truong L, Gatuz JL, Patel K, Ghosh AK, Johnson ME. ChemMedChem 8 1361-1372 (2013)
  8. Alzheimer's Disease is Driven by Intraneuronally Retained Beta-Amyloid Produced in the AD-Specific, βAPP-Independent Pathway: Current Perspective and Experimental Models for Tomorrow. Volloch V, Olsen B, Rits S. Ann Integr Mol Med 2 90-114 (2020)
  9. AD "Statin": Alzheimer's Disorder is a "Fast" Disease Preventable by Therapeutic Intervention Initiated Even Late in Life and Reversible at the Early Stages. Volloch V, Olsen BR, Rits S. Ann Integr Mol Med 2 75-89 (2020)
  10. NMR quality control of fragment libraries for screening. Sreeramulu S, Richter C, Kuehn T, Azzaoui K, Blommers MJJ, Del Conte R, Fragai M, Trieloff N, Schmieder P, Nazaré M, Specker E, Ivanov V, Oschkinat H, Banci L, Schwalbe H. J Biomol NMR 74 555-563 (2020)
  11. Precursor-Independent Overproduction of Beta-Amyloid in AD: Mitochondrial Dysfunction as Possible Initiator of Asymmetric RNA-Dependent βAPP mRNA Amplification. An Engine that Drives Alzheimer's Disease. Volloch V, Olsen BR, Rits S. Ann Integr Mol Med 1 61-74 (2019)
  12. Virtual and biophysical screening targeting the γ-tubulin complex--a new target for the inhibition of microtubule nucleation. Cala O, Remy MH, Guillet V, Merdes A, Mourey L, Milon A, Czaplicki G. PLoS One 8 e63908 (2013)
  13. Virtual screening and structure-based discovery of indole acylguanidines as potent β-secretase (BACE1) inhibitors. Zou Y, Li L, Chen W, Chen T, Ma L, Wang X, Xiong B, Xu Y, Shen J. Molecules 18 5706-5722 (2013)
  14. Effect of sampling on BACE-1 ligands binding free energy predictions via MM-PBSA calculations. Chéron N, Shakhnovich EI. J Comput Chem 38 1941-1951 (2017)
  15. Alzheimer's disease: identification and development of β-secretase (BACE-1) binding fragments and inhibitors by dynamic ligation screening (DLS). Fernández-Bachiller MI, Horatscheck A, Lisurek M, Rademann J. ChemMedChem 8 1041-1056 (2013)
  16. BcL-xL conformational changes upon fragment binding revealed by NMR. Aguirre C, Ten Brink T, Walker O, Guillière F, Davesne D, Krimm I. PLoS One 8 e64400 (2013)
  17. Target specific proteochemometric model development for BACE1 - protein flexibility and structural water are critical in virtual screening. Manoharan P, Chennoju K, Ghoshal N. Mol Biosyst 11 1955-1972 (2015)
  18. ACFIS 2.0: an improved web-server for fragment-based drug discovery via a dynamic screening strategy. Shi XX, Wang ZZ, Wang F, Hao GF, Yang GF. Nucleic Acids Res 51 W25-W32 (2023)
  19. Discovery of potent iminoheterocycle BACE1 inhibitors. Caldwell JP, Mazzola RD, Durkin J, Chen J, Chen X, Favreau L, Kennedy M, Kuvelkar R, Lee J, McHugh N, McKittrick B, Orth P, Stamford A, Strickland C, Voigt J, Wang L, Zhang L, Zhang Q, Zhu Z. Bioorg Med Chem Lett 24 5455-5459 (2014)
  20. Effect of pH and ligand charge state on BACE-1 fragment docking performance. Domínguez JL, Villaverde MC, Sussman F. J Comput Aided Mol Des 27 403-417 (2013)
  21. Iminopyrimidinones: a novel pharmacophore for the development of orally active renin inhibitors. McKittrick BA, Caldwell JP, Bara T, Boykow G, Chintala M, Clader J, Czarniecki M, Courneya B, Duffy R, Fleming L, Giessert R, Greenlee WJ, Heap C, Hong L, Huang Y, Iserloh U, Josien H, Khan T, Korfmacher W, Liang X, Mazzola R, Mitra S, Moore K, Orth P, Rajagopalan M, Roy S, Sakwa S, Strickland C, Vaccaro H, Voigt J, Wang H, Wong J, Zhang R, Zych A. Bioorg Med Chem Lett 25 1592-1596 (2015)
  22. Retrospective molecular docking study of WY-25105 ligand to β-secretase and bias of the three-dimensional structure flexibility. Ghemtio L, Muzet N. J Mol Model 19 2971-2979 (2013)
  23. Thermodynamic and kinetic characterization of hydroxyethylamine β-secretase-1 inhibitors. Mondal K, Regnstrom K, Morishige W, Barbour R, Probst G, Xu YZ, Artis DR, Yao N, Beroza P, Bova MP. Biochem Biophys Res Commun 441 291-296 (2013)
  24. A fluorescent approach for identifying P2X1 ligands. Ruepp MD, Brozik JA, de Esch IJ, Farndale RW, Murrell-Lagnado RD, Thompson AJ. Neuropharmacology 98 13-21 (2015)
  25. 2,2,2-Trifluoroethyl-thiadiazines: a patent evaluation of WO2016023927. Dotsenko VV, Chigorina EA, Krivokolysko SG. Expert Opin Ther Pat 26 1371-1376 (2016)
  26. Network Models of BACE-1 Inhibitors: Exploring Structural and Biochemical Relationships. Akgüller Ö, Balcı MA, Cioca G. Int J Mol Sci 25 6890 (2024)


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