Drug Res (Stuttg) 2019; 69(08): 451-457
DOI: 10.1055/a-0849-9377
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Molecular Docking and 3D Qsar Studies of C000000956 as a Potent Inhibitor of Bace-1[*]

Ogunleye Adewale Joseph
1   Centre for Biocomputing and Drug Development, Adekunle Ajasin University, Akungba Akoko, Ondo State Nigeria
,
Kikiowo Babatomiwa
1   Centre for Biocomputing and Drug Development, Adekunle Ajasin University, Akungba Akoko, Ondo State Nigeria
,
Adelakun Niyi
1   Centre for Biocomputing and Drug Development, Adekunle Ajasin University, Akungba Akoko, Ondo State Nigeria
,
Omotuyi Olaposi
1   Centre for Biocomputing and Drug Development, Adekunle Ajasin University, Akungba Akoko, Ondo State Nigeria
2   Department of Biochemistry, Adekunle Ajasin University, Akungba Akoko, Ondo State Nigeria
,
Inyang Olumide
1   Centre for Biocomputing and Drug Development, Adekunle Ajasin University, Akungba Akoko, Ondo State Nigeria
› Author Affiliations
Further Information

Publication History

received 26 March 2018

accepted 24 January 2019

Publication Date:
19 February 2019 (online)

Abstract

Background BACE-1 is an aspartate protease that is responsible for the proteolysis of amyloid precursor proteins (APP) into beta-amyloid (Aβ), a neurotoxic peptide in patients with Alzheimer’s disease (AD). As such, BACE-1 is a prime pharmacological target in the control of Aβ in the brain and its inhibition will be a sound approach in AD therapy.

Methods The computational pipeline which comprised molecular docking (MD), Quantitative Structure Activity Relationship (QSAR) modelling and Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) studies enabled the prediction of molecular interaction and relative inhibitory potentials of the hit compound.

Results and Discussion The current study reports a naturally sourced small molecule inhibitor of BACE1 (C000000956) which was obtained through a computational pipeline. Also, pharmacological constraints such as pH dependent activity of the enzyme and blood brain barrier permeation which have been associated with the efficacy of previous BACE-1 inhibitors were well catered for. Our results suggest that orally delivered C000000956 is a potential small molecule inhibitor of BACE-1 which may find usefulness in AD-therapy.

* This work was carried out at the Centre for Biocomputing and Drug Development, Adekunle Ajasin University, Akungba Akoko, Ondo state.


 
  • References

  • 1 Frank ML. Amyloid-Beta and Tau in Alzheimer’s Disease. Nature Reviews Neuroscience 2008 (Poster)
  • 2 Pinhiero AA, Silva KRd, Silva AES. et al In silico identification of novel potential bace-1 inhibitors for alzheimer’s disease treatment: Molecular docking, pharmacophore modeling and activity and synthetic accessibility predictions. British Journal of Pharmaceutical Research 2015; 7: 217-229
  • 3 Ghosh AK, Bilcer G, Hong L. et al. Memapsin 2 (beta-secretase) inhibitor drug, between fantasy and reality. Curr Alzheimer Res 2007; 4: 418-422
  • 4 Wolfe MS. Gamma-Secretase inhibitors and modulators for Alzheimer’s disease. J Neurochem. 2012; 120 (Suppl. 01) 89-98 PubMed PMID: 22122056. Pubmed Central PMCID: 3254709
  • 5 Lalitha K, Rajendra Kulothungan S. Selective determination of mimosine and its dihydroxypyridinyl derivative in plant systems. Amino acids. 2006; 31: 279-287 PubMed PMID: 16988910.
  • 6 Harun A, James RM, Lim SM. et al. BACE1 inhibitory activity of fungal endophytic extracts from Malaysian medicinal plants. BMC complementary and alternative medicine 2011; 11: 79 PubMed PMID: 21943123. Pubmed Central PMCID: 3197562
  • 7 Brodney MA, Barreiro G, Ogilvie K. et al. Spirocyclic sulfamides as β-secretase 1 (bace-1) inhibitors for the treatment of alzheimer’s disease: utilization of structure based drug design, watermap, and cns penetration studies to identify centrally efficacious inhibitors. Journal of Medicinal Chemistry 2012; 55: 9224-9239
  • 8 Deganutti G, Moro S. Estimation of kinetic and thermodynamic ligand-binding parameters using computational strategies. Future Med Chem 2017; 0224
  • 9 Gohlke H, Klebe G. Approaches to the description and prediction of the binding affinity of small-molecule ligands to macromolecular receptors. Angew Chem Int Ed 2002; 41: 33
  • 10 Almi Z, Belaidi S, Lanez T. et al. Structure Activity Relationships, QSAR Modeling and Drug-like Calculations of TP Inhibition of 1,3,4-oxadiazoline-2-thione Derivatives. International Letters of Chemistry, Physics and Astronomy 2013; 37: 113-124
  • 11 Roy K, Kar S, Das RN. Statistical methods in QSAR/QSPR. 2015; 37-59
  • 12 Ogunleye AJ, Eniafe GO, Inyang OK. et al. Salient aspects of PBP2A-Inhibition: A QSAR study. Current Computer Aided Drug Design 2018; 363-369
  • 13 Pirhadi S, Shiri F, Ghasemi JB. Multivariate statistical analysis methods in QSAR. RSC Adv 2015; 5: 104635-104665
  • 14 Yechun X, Min-jun L, Harry G. et al. Flexibility of the flap in the active site of BACE1 as revealed by crystal structures and molecular dynamics simulations. Acta Crystallographica 2013; D68: 12
  • 15 Lin YC, Wang CC, Chen IS. et al. TIPdb: A database of anticancer, antiplatelet, and antituberculosis phytochemicals from indigenous plants in Taiwan. TheScientificWorldJournal 2013; 2013: 736386 PubMed PMID: 23766708. Pubmed Central PMCID: 3666282
  • 16 Shimizu H, Tosaki A, Kaneko K. et al. Crystal structure of an active form of BACE1, an enzyme responsible for amyloid beta protein production. Molecular and cellular biology 2008; 28: 3663-3671 PubMed PMID: 18378702. Pubmed Central PMCID: 2423307
  • 17 Christopher AL, Franco L, Beryl WD. et al. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development setting. Advanced Drug delivery Reviews 2001; 46: 24
  • 18 Charrier N, Clarke B, Cutler L. et al. Second generation of BACE-1 inhibitors. Part 1: The need for improved pharmacokinetics. Bioorganic & medicinal chemistry letters 2009; 19: 3664-3668 PubMed PMID: 19428244
  • 19 Scholefield Z, Yates E, Wayne G. et al. Heparan sulfate regulates ayloid precursor protein processing by BACE1, the Alzheimer's Beta Secretase. The Journal of cell biology 2003; 163: 97-107
  • 20 Eaton HL, Wyss DF. Effective Progreession of Nuclear Magnetic Resonance-Detected Fragment Hits. Kuo LC. (editor.) United Kingdoms: Elsievier, Inc; 2011: 22 p
  • 21 Hossain MU, Khan MA, Rakib-Uz-Zaman SM. et al. treating diabetes mellitus: pharmacophore based designing of potential drugs fromgymnema sylvestreagainst insulin receptor protein. BioMed research international 2016; 2016: 1-14
  • 22 Kraynov E, Kamath AV, Walles M. et al. current approaches for absorption, distribution, metabolism, and excretion characterization of antibody-drug conjugates: an industry white paper. Drug Metabolism and Disposition 2016; 44: 617-623
  • 23 Johann G, Mario M. Iterative partial equalization of orbital electronegativity—A rapid access to atomic charges. Tetrahedron. 1979; 36: 3219-3228
  • 24 Galvez J, Garcia R, Salabert MT. et al. Charge Indexes. New Topological Descriptors. Journal of Chemical Information and Computer Sciences 1994; 1994/05/01 34: 520-525