Tags

Type your tag names separated by a space and hit enter

Investigation of naphthofuran moiety as potential dual inhibitor against BACE-1 and GSK-3β: molecular dynamics simulations, binding energy, and network analysis to identify first-in-class dual inhibitors against Alzheimer's disease.
J Mol Model. 2017 Aug; 23(8):239.JM

Abstract

BACE-1 and GSK-3β are potential therapeutic drug targets for Alzheimer's disease. Recently, both the targets received attention for designing dual inhibitors for Alzheimer's disease. Until now, only two-scaffold triazinone and curcumin have been reported as BACE-1 and GSK-3β dual inhibitors. Docking, molecular dynamics, clustering, binding energy, and network analysis of triazinone derivatives with BACE-1 and GSK-3β was performed to get molecular insight into the first reported dual inhibitor. Further, we designed and evaluated a naphthofuran series for its ability to inhibit BACE-1 and GSK-3β with the computational approaches. Docking study of naphthofuran series showed a good binding affinity towards both the targets. Molecular dynamics, binding energy, and network analysis were performed to compare their binding with the targets and amino acids responsible for binding. Naphthofuran series derivatives showed good interaction within the active site residues of both of the targets. Hydrogen bond occupancy and binding energy suggested strong binding with the targets. Dual-inhibitor binding was mostly governed by the hydrophobic interactions for both of the targets. Per residue energy decomposition and network analysis identified the key residues involved in the binding and inhibiting BACE-1 and GSK-3β. The results indicated that naphthofuran series derivative 11 may be a promising first-in-class dual inhibitor against BACE-1 and GSK-3β. This naphthofuran series may be further explored to design better dual inhibitors. Graphical abstract Naphthofuran derivative as a dual inhibitor for BACE-1 and GSK-3β.

Links

Publisher Full Text (DOI)

Authors+Show Affiliations

Kumar A
Biotechnology Division, CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow, UP, 226015, India.
Srivastava G
Biotechnology Division, CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow, UP, 226015, India.
Srivastava S
Biotechnology Division, CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow, UP, 226015, India.
Verma S
Chemical Sciences Division, CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow, UP, 226015, India.
Negi AS
Chemical Sciences Division, CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow, UP, 226015, India.
Sharma A
Biotechnology Division, CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow, UP, 226015, India. ashoksharma@cimap.res.in.

MeSH

Alzheimer DiseaseAmyloid Precursor Protein SecretasesAspartic Acid EndopeptidasesCluster AnalysisComputational BiologyFuransGlycogen Synthase Kinase 3 betaHumansMolecular Docking SimulationMolecular Dynamics SimulationNaphthalenes

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28741112

Citation

Kumar, Akhil, et al. "Investigation of Naphthofuran Moiety as Potential Dual Inhibitor Against BACE-1 and GSK-3β: Molecular Dynamics Simulations, Binding Energy, and Network Analysis to Identify First-in-class Dual Inhibitors Against Alzheimer's Disease." Journal of Molecular Modeling, vol. 23, no. 8, 2017, p. 239.
Kumar A, Srivastava G, Srivastava S, et al. Investigation of naphthofuran moiety as potential dual inhibitor against BACE-1 and GSK-3β: molecular dynamics simulations, binding energy, and network analysis to identify first-in-class dual inhibitors against Alzheimer's disease. J Mol Model. 2017;23(8):239.
Kumar, A., Srivastava, G., Srivastava, S., Verma, S., Negi, A. S., & Sharma, A. (2017). Investigation of naphthofuran moiety as potential dual inhibitor against BACE-1 and GSK-3β: molecular dynamics simulations, binding energy, and network analysis to identify first-in-class dual inhibitors against Alzheimer's disease. Journal of Molecular Modeling, 23(8), 239. https://doi.org/10.1007/s00894-017-3396-7
Kumar A, et al. Investigation of Naphthofuran Moiety as Potential Dual Inhibitor Against BACE-1 and GSK-3β: Molecular Dynamics Simulations, Binding Energy, and Network Analysis to Identify First-in-class Dual Inhibitors Against Alzheimer's Disease. J Mol Model. 2017;23(8):239. PubMed PMID: 28741112.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Investigation of naphthofuran moiety as potential dual inhibitor against BACE-1 and GSK-3β: molecular dynamics simulations, binding energy, and network analysis to identify first-in-class dual inhibitors against Alzheimer's disease. AU - Kumar,Akhil, AU - Srivastava,Gaurava, AU - Srivastava,Swati, AU - Verma,Seema, AU - Negi,Arvind S, AU - Sharma,Ashok, Y1 - 2017/07/24/ PY - 2016/12/13/received PY - 2017/06/25/accepted PY - 2017/7/26/entrez PY - 2017/7/26/pubmed PY - 2018/9/11/medline KW - Alzheimer’s disease KW - BACE-1 and GSK-3β KW - Binding energy analysis KW - Dual inhibitor KW - Molecular dynamics simulation KW - Network analysis SP - 239 EP - 239 JF - Journal of molecular modeling JO - J Mol Model VL - 23 IS - 8 N2 - BACE-1 and GSK-3β are potential therapeutic drug targets for Alzheimer's disease. Recently, both the targets received attention for designing dual inhibitors for Alzheimer's disease. Until now, only two-scaffold triazinone and curcumin have been reported as BACE-1 and GSK-3β dual inhibitors. Docking, molecular dynamics, clustering, binding energy, and network analysis of triazinone derivatives with BACE-1 and GSK-3β was performed to get molecular insight into the first reported dual inhibitor. Further, we designed and evaluated a naphthofuran series for its ability to inhibit BACE-1 and GSK-3β with the computational approaches. Docking study of naphthofuran series showed a good binding affinity towards both the targets. Molecular dynamics, binding energy, and network analysis were performed to compare their binding with the targets and amino acids responsible for binding. Naphthofuran series derivatives showed good interaction within the active site residues of both of the targets. Hydrogen bond occupancy and binding energy suggested strong binding with the targets. Dual-inhibitor binding was mostly governed by the hydrophobic interactions for both of the targets. Per residue energy decomposition and network analysis identified the key residues involved in the binding and inhibiting BACE-1 and GSK-3β. The results indicated that naphthofuran series derivative 11 may be a promising first-in-class dual inhibitor against BACE-1 and GSK-3β. This naphthofuran series may be further explored to design better dual inhibitors. Graphical abstract Naphthofuran derivative as a dual inhibitor for BACE-1 and GSK-3β. SN - 0948-5023 UR - https://www.unboundmedicine.com/medline/citation/28741112/Investigation_of_naphthofuran_moiety_as_potential_dual_inhibitor_against_BACE_1_and_GSK_3β:_molecular_dynamics_simulations_binding_energy_and_network_analysis_to_identify_first_in_class_dual_inhibitors_against_Alzheimer's_disease_ L2 - https://dx.doi.org/10.1007/s00894-017-3396-7 DB - PRIME DP - Unbound Medicine ER -