Sulfonamido, amido heterocyclic adducts of tetrazole derivatives as BACE1 inhibitors: in silico exploration.

Publisher: ESCOM Science Publishers Country of Publication: Netherlands NLM ID: 9516534 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1573-501X (Electronic) Linking ISSN: 13811991 NLM ISO Abbreviation: Mol Divers Subsets: MEDLINE

Original Publication: Leiden, The Netherlands : ESCOM Science Publishers, c1995-

Amyloid Precursor Protein Secretases*/antagonists & inhibitors ; Amyloid Precursor Protein Secretases*/chemistry ; Amyloid Precursor Protein Secretases*/metabolism ; Tetrazoles*/chemistry ; Tetrazoles*/pharmacology ; Aspartic Acid Endopeptidases*/antagonists & inhibitors ; Aspartic Acid Endopeptidases*/chemistry ; Aspartic Acid Endopeptidases*/metabolism ; Molecular Docking Simulation* ; Molecular Dynamics Simulation*; Humans ; Sulfonamides/chemistry ; Sulfonamides/pharmacology ; Structure-Activity Relationship ; Protease Inhibitors/chemistry ; Protease Inhibitors/pharmacology ; Ligands ; Computer Simulation ; Heterocyclic Compounds/chemistry ; Heterocyclic Compounds/pharmacology ; Alzheimer Disease/drug therapy

Alzheimer's disease is a neurodegenerative disorder accounting for 60-80% of dementia cases and is accompanied by a high mortality rate in patients above 70 years of age. The formation of senile plaques composed of amyloid-β protein is a hallmark of Alzheimer's disease. Beta-site APP cleaving enzyme 1 (BACE1) is a proteolytic enzyme involved in the degradation of amyloid precursor protein, which further degrades to form toxic amyloid-β fragments. Hence, inhibition of BACE1 was stated to be an effective strategy for Alzheimer's therapeutics. Keeping in mind the structures of different BACE1 inhibitors that had reached the clinical trials, we designed a library of compounds (total 164) based on a substituted 5-amino tetrazole scaffold which was an isosteric replacement of the cyclic amidine moiety, a common component of the BACE1 inhibitors which reached the clinical trials. The scaffold was linked to different structural moieties with the aid of an amide or sulfonamide bond to design some novel molecules. Molecular docking was initially performed and the top 5 molecules were selected based on docking scores and protein-ligand interactions. Furthermore, molecular dynamic simulations were performed for these molecules (3g, 7k, 8n, 9d, 9g) for 100 ns and MM-GBSA calculations were performed for each of these complexes. After critical evaluation of the obtained results, three potential molecules (9d, 8n, and 7k) were forwarded for prolonged stability studies by performing molecular dynamic simulations for 250 ns and simultaneous MM-GBSA calculations. It was observed that the compounds (9d, 8n, and 7k) were forming good interactions with the amino acid residues of the catalytic site of the enzyme with multiple non-covalent interactions. In MD simulations, the compounds have shown better stability and better binding energy throughout the runtime.
Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests.
(© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

2023 Alzheimer’s disease facts and figures. Alzheimer’s & Dementia.; Available from: https://www.alz.org.
Maia MA, Sousa E. BACE-1, and γ-secretase as therapeutic targets for Alzheimer’s disease (2019). Vol. 12(1):41, Pharmaceuticals. MDPI AG; Available from: https://doi.org/10.3390/ph12010041.
Qizilbash N, Birks J, López Arrieta J, Lewington S, Szeto S, WITHDRAWN: Tacrine for Alzheimer’s disease, (2007) 3, Cochrane Database of Systematic Reviews, Cochrane Library. Available from. https://doi.org/10.1002/14651858.cd000202. (PMID: 10.1002/14651858.cd000202)
Cummings J, Zhou Y, Lee G, Zhong K, Fonseca J, Cheng F. Alzheimer’s disease drug development pipeline: 2023 (2023), Vol. 9(2):e12385, Alzheimer’s Dementia, Wiley; Available from: https://doi.org/10.1002/trc2.12385.
Alhazmi HA, Albratty M. An update on the novel and approved drugs for Alzheimer's disease (2022), Vol. 30 (12), Saudi Pharmaceutical Journal. Elsevier B.V.; Available from: https://doi.org/10.1016/j.jsps.2022.10.004.
Brockmann R, Nixon J, Love BL, Yunusa I. Impacts of FDA approval and Medicare restriction on anti-amyloid therapies for Alzheimer’s disease: patient outcomes, healthcare costs, and drug development (2023), Vol. 20 (100467), Lancet Regional Health - Americas. Elsevier Ltd; Available from: https://doi.org/10.1016/j.lana.2023.
Verger A, Yakushev I, Albert NL, van Berckel B, Brendel M, Cecchin D, et al. FDA approval of lecanemab: the real start of widespread amyloid PET use? — the EANM Neuroimaging Committee perspective (2023), Vol. 50, European Journal of Nuclear Medicine and Molecular Imaging. Springer Science and Business Media Deutschland GmbH; Available from: https://doi.org/10.1007/s00259-023-06177-5.
Sun J, Roy S. The physical approximation of APP and BACE-1: A key event in Alzheimer’s disease pathogenesis (2018), Vol. 78 (3), Developmental Neurobiology. John Wiley and Sons Inc.; Available from: https://doi.org/10.1002/dneu.22556.
Cole SL, Vassar R. The Alzheimer’s disease β-secretase enzyme, BACE1 (2007), Vol. 2 (22), Molecular Neurodegeneration, BioMed Central; Available from: https://doi.org/10.1186/1750-1326-2-22.
Gehlot P, Kumar S, Kumar Vyas V, Singh Choudhary B, Sharma M, Malik R. Guanidine-based β amyloid precursor protein cleavage enzyme 1 (BACE-1) inhibitors for the Alzheimer’s disease (AD): A review (2022), Vol. 74:117047, Bioorganic Medicinal Chemistry, Elsevier; Available from: https://doi.org/10.1016/j.bmc.2022.117047.
Munj SM, Patil PB. Drug Discovery to Drug Development of BACE1 Inhibitor as Anti-Alzheimer’s: A Review (2022), Vol. 23(2), Current Topics in Medicinal Chemistry, Bentham Sciences; Available from: https://doi.org/10.2174/1568026623666221228140450.
Miranda A, Montiel E, Ulrich H, Paz C, Ferreira S. Selective Secretase Targeting for Alzheimer’s Disease Therapy (2021), Vol. 81 (1), Journal of Alzheimer’s Disease, IOS Press BV; Available from: https://doi.org/10.3233/JAD-201027.
Oehlrich D, Peschiulli A, Tresadern G, Van Gool M, Vega JA, De Lucas AI, et al. Evaluation of a Series of β-Secretase 1 Inhibitors Containing Novel Heteroaryl-Fused-Piperazine Amidine Warheads (2018), Vol. 10(8), ACS Medicinal Chemistry Letters, American Chemical Society; Available from: https://doi.org/10.1021/acsmedchemlett.9b00181.
Das B, Yan R. A Close Look at BACE1 Inhibitors for Alzheimer’s Disease Treatment (2019), Vol. 33 (3), CNS Drugs, Springer International Publishing; Available from: https://doi.org/10.1007/s40263-019-00613-7.
Rombouts F, Kusakabe K ichi, Hsiao CC, Gijsen HJM. Small-molecule BACE1 inhibitors: a patent literature review (2011 to 2020) (2021), Vol. 31 (1), Expert Opinion on Therapeutic Patents, Taylor and Francis Ltd.; Available from: https://doi.org/10.1080/13543776.2021.1832463.
Zou Y, Li L, Chen W, Chen T, Ma L, Wang X, et al. Virtual screening and structure-based discovery of indole acyl guanidines as potent β-secretase (BACE1) inhibitors (2013), Vol. 18(5):5706–22, Molecules, MDPI; Available from: https://doi.org/10.3390/molecules18055706.
Ali S, Bin AMHH, Khan F, Murtaza G, Rizvanov AA, Iqbal J, Evaluation B, of Newly Synthesized Biaryl Guanidine Derivatives to Arrest β -Secretase Enzymatic Activity Involved in Alzheimer’s Disease, et al (2020) Article number 8934289, BioMed Research International. Hindawi; Available from. https://doi.org/10.1155/2020/8934289. (PMID: 10.1155/2020/8934289)
Polgár T, Keserü GM. Virtual screening for β-secretase (BACE1) inhibitors reveals the importance of protonation states at Asp32 and Asp228 (2005), Vol. 48(11), Journal of Medicinal Chemistry, American Chemical Society; Available from: https://doi.org/10.1021/jm049133b.
Liu S, Fu R, Cheng X, Chen SP, Zhou LH. Exploring the binding of BACE-1 inhibitors using comparative binding energy analysis (COMBINE) (2012), Vol. 12 (21), BMC Structural Biology, BioMed Central; Available from: https://doi.org/10.1186/1472-6807-12-21.
Tuccinardi T. What is the current value of MM/PBSA and MM/GBSA methods in drug discovery? (2021), Vol. 16 (11), Expert Opinion on Drug Discovery, Taylor and Francis Ltd.; Available from: https://doi.org/10.1080/17460441.2021.1942836.
Ongaro A, Oselladore E, Memo M, Ribaudo G, Gianoncelli A. Insight into the LFA-1/SARS-CoV-2 Orf7a Complex by Protein-Protein Docking, Molecular Dynamics, and MM-GBSA Calculations (2021), Vol. 61(6), Journal of Chemical Information and Modeling, American Chemical Society; Available from: https://doi.org/10.1021/acs.jcim.1c00198.
Basnet S, Ghimire MP, Lamichhane TR, Adhikari R, Adhikari A. Identification of potential human pancreatic αamylase inhibitors from natural products by molecular docking, MM/GBSA calculations, MD simulations, and ADMET analysis (2023), Vol. 18(3):e0275765 PLOS ONE; Available from: https://doi.org/10.1371/journal.pone.0275765.
Zhao J, Liu X, Xia W, Zhang Y, Wang C. Targeting Amyloidogenic Processing of APP in Alzheimer’s Disease (2020), Vol. 13, Frontiers in Molecular Neuroscience, Frontiers Media S.A.; Available from: https://doi.org/10.3389/fnmol.2020.00137.
Zhang X, Song W. The role of APP and BACE1 trafficking in APP processing and amyloid-β generation (2013), Vol. 5 (46), Alzheimer’s research and Therapy, BioMed Central, Available from: https://doi.org/10.1186/alzrt211.
Das B, Yan R. A Close Look at BACE1 Inhibitors for Alzheimer’s Disease Treatment (2019), Vol. 33 (3), CNS Drugs. Springer International Publishing; Available from: https://doi.org/10.1007/s40263-019-00613-7.
Ghosh AK, Osswald HL. BACE1 (β-secretase) inhibitors for the treatment of Alzheimer’s disease (2014), Vol. 43 (19), Chemical Society Reviews. Royal Society of Chemistry; Available from: https://doi.org/10.1039/c3cs60460h.
Barman A, Prabhakar R. Elucidating the catalytic mechanism of β-secretase (BACE1): A quantum mechanics/molecular mechanics (QM/MM) approach, Vol. 40, Journal of Molecular Graphics and Modeling, Elsevier; Available from: https://doi.org/10.1016/j.jmgm.2012.12.010.
Yen YC, Kammeyer AM, Jensen KC, Tirlangi J, Ghosh AK, Mesecar AD. Development of an Efficient Enzyme Production and Structure-Based Discovery Platform for BACE1 Inhibitors HHS Public Access (2019), Vol. 58(44), Biochemistry, American Chemical Society; Available from: https://doi.org/10.1021/acs.biochem.9b00714.
Mouchlis VD, Melagraki G, Zacharia LC, Afantitis A. Computer-aided drug design of β-secretase, γ- secretase and anti-tau inhibitors for the discovery of novel Alzheimer’s therapeutics (2020), Vol. 21 (3), International Journal of Molecular Sciences, MDPI AG; Available from: https://doi.org/10.3390/ijms21030703.
Cosconati S, Marinelli L, Di Leva FS, La Pietra V, De Simone A, Mancini F, et al. Protein flexibility in virtual screening: The BACE-1 case study (2012), Vol. 52(10), Journal of Chemical Information and Modeling, American Chemical Society; Available from: https://doi.org/10.1021/ci300390h.
Xu Y, Li MJ, Greenblatt H, Chen W, Paz A, Dym O, et al. Flexibility of the flap in the active site of BACE1 as revealed by crystal structures and molecular dynamics simulations (2012), Vol. 68 (1), Acta Crystallographica Section D Biological Crystallography, International Union of Crystallography; Available from: https://doi.org/10.1107/s0907444911047251.
Shimizu H, Tosaki A, Kaneko K, Hisano T, Sakurai T, Nukina N. Crystal Structure of an Active Form of BACE1, an Enzyme Responsible for Amyloid β Protein Production (2008), Vol. 28 (11), Molecular and Cellular Biology, Taylor and Francis; Available from: https://doi.org/10.1128/MCB.02185-07.

Keywords: Alzheimer’s disease; BACE1 inhibitors; Molecular docking; Molecular dynamics; Tetrazoles

EC 3.4.- (Amyloid Precursor Protein Secretases)
0 (Tetrazoles)
EC 3.4.23.- (Aspartic Acid Endopeptidases)
EC 3.4.23.46 (BACE1 protein, human)
0 (Sulfonamides)
0 (Protease Inhibitors)
0 (Ligands)
0 (Heterocyclic Compounds)

Date Created: 20240124 Date Completed: 20241220 Latest Revision: 20241220

20241220

10.1007/s11030-023-10792-7

38267751