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Conformational analysis, molecular structure, spectroscopic, NBO, reactivity descriptors, wavefunction and molecular docking investigations of 5,6-dimethoxy-1-indanone: A potential anti Alzheimer's agent.

ABSTRACT: The objective of the present study is focused to elucidate the structure of potential anti-Alzheimer's compound 5,6-Dimethoxy-1-indanone (5,6-DMI) and study its binding interaction towards the active site by molecular docking studies. The structural and various spectroscopic tools are used to understand the various interaction behaviors of the title compound. The theoretical calculation of 5,6-DMI molecule is computed by Gaussian 09W software with Density functional B3LYP and CAM-B3LYP method utilizing 6-311G(d,p) as basis set. The Natural Bond Orbital (NBO) analysis has been performed to find all possible transition was correlate with electronic transition. The Non covalent interaction of 5,6-DMI molecule was examined by adopt Reduced Density Gradient (RDG) analysis and colour filled ELF diagram. Molecular docking results suggest that 5,6-DMI may exhibit inhibitory activity against apoE protein and may act as potential against Alzheimer's disease.

SUBMITTER: Sebastian S

PROVIDER: S-EPMC8808071 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Conformational analysis, molecular structure, spectroscopic, NBO, reactivity descriptors, wavefunction and molecular docking investigations of 5,6-dimethoxy-1-indanone: A potential anti Alzheimer's agent.

Sebastian S S Sylvestre S S Sundaraganesan N N Karthikeyan B B Silvan S S

Heliyon 20220123 1

The objective of the present study is focused to elucidate the structure of potential anti-Alzheimer's compound 5,6-Dimethoxy-1-indanone (5,6-DMI) and study its binding interaction towards the active site by molecular docking studies. The structural and various spectroscopic tools are used to understand the various interaction behaviors of the title compound. The theoretical calculation of 5,6-DMI molecule is computed by Gaussian 09W software with Density functional B3LYP and CAM-B3LYP method ut ...[more]

PMID: 35128106

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Project description:BackgroundsAlzheimer's disease (AD) is a multifactorial neurodegenerative disease. The treatment of AD through multiple pathological targets may generate therapeutic efficacy better. The multifunctional molecules that simultaneously hit several pathological targets have been of great interest in the intervention of AD.MethodsHere, we combined the chalcone scaffold with carbamate moiety and 5,6-dimethoxy-indanone moiety to generate a novel multi-target-directed ligand (MTDL) molecule (E)-3-((5,6-dimethoxy-1-oxo-1,3-dihydro-2H-inden-2-ylidene)-methyl)phenylethyl(methyl) carbamate (named AP5). In silico approaches were used to virtually predict the binding interaction of AP5 with AChE, the drug-likeness, and BBB penetrance, and later validated by evaluation of pharmacokinetics (PK) in vivo by LC-MS/MS. Moreover, studies were conducted to examine the potential of AP5 for inhibiting AChE and AChE-induced amyloid-β (Aβ) aggregation, attenuating neuroinflammation, and providing neuroprotection in the APP/PS1 model of AD.ResultsWe found that AP5 can simultaneously bind to the peripheral and catalytic sites of AChE by molecular docking. AP5 exhibited desirable pharmacokinetic (PK) characteristics including oral bioavailability (67.2%), >10% brain penetrance, and favorable drug-likeness. AP5 inhibited AChE activity and AChE-induced Aβ aggregation in vivo and in vitro. Further, AP5 lowered Aβ plaque deposition and insoluble Aβ levels in APP/PS1 mice. Moreover, AP5 exerted anti-inflammatory responses by switching microglia to a disease-associated microglia (DAM) phenotype and preventing A1 astrocytes formation. The phagocytic activity of microglial cells to Aβ was recovered upon AP5 treatment. Importantly, chronic AP5 treatment significantly prevented neuronal and synaptic damage and memory deficits in AD mice.ConclusionTogether, our work demonstrated that AP5 inhibited the AChE activity, decreased Aβ plaque deposition by interfering Aβ aggregation and promoting microglial Aβ phagocytosis, and suppressed inflammation, thereby rescuing neuronal and synaptic damage and relieving cognitive decline. Thus, AP5 can be a new promising candidate for the treatment of AD.

Project description:ContextHydrogen bonds critically influence the structure and properties of both organic molecules and biomolecules, as well as supramolecular assemblies. For this reason, the development and elaboration of methods for quantitative assessment of hydrogen bond energy is an urgent challenge. In this study, using a large series of hydroxycarbonyl aliphatic compounds with the O‒H···O = C intramolecular hydrogen bond, a bank of hydrogen bond descriptors was created, including spectroscopic, structural, QTAIM-based, and NBO-based parameters. It was shown that the O‒H vibration frequency, OH chemical shift as the spectroscopic descriptors, the O···H hydrogen bond length, O···O distance, and O‒H covalent bond length as the structural descriptors, the electron density and its Laplacian, electron potential energy density in the hydrogen bond critical point, the electron density at the ring critical point as the QTAIM-based descriptors change in a correlated manner. The same correlation is found in change of the charge transfer energy through a hydrogen bond, the occupancy of the O‒H bond antibonding orbital, the Wiberg indices of the O···H hydrogen bond, and the O‒H covalent bond, as well as the polarization of the O‒H bond, which are the NBO-based descriptors. It was also recognized that the specified descriptors from the spectroscopic, structural, QTAIM-based, and NBO-based categories are functionally related to the values of intramolecular hydrogen bond energy, quantified via the molecular tailoring approach. This allowed one to obtain a system of equations for quantitative estimation of intramolecular hydrogen bond energy based on the spectroscopic, structural, QTAIM, and NBO descriptors, which makes such quantification more dependable and reliable.MethodsTo obtain the spectroscopic descriptors, the vibrational spectra and shielding constants were calculated using the GIAO method. Structural descriptors were obtained for the equilibrium geometry of molecules, calculated at the MP2(FC)/6-311 + + (2d,2p) level using the Gaussian 09 program. The QTAIM-based descriptors were calculated using the AIMAll program within the framework of the quantum theory "Atoms in Molecules." The NBO-based descriptors were calculated using the NBO 3.1 program implemented into Gaussian 09. To quantify the energy of intramolecular hydrogen bonds, molecular fragmentation was used within the molecular tailoring approach.

Dataset Information

Conformational analysis, molecular structure, spectroscopic, NBO, reactivity descriptors, wavefunction and molecular docking investigations of 5,6-dimethoxy-1-indanone: A potential anti Alzheimer's agent.

Publications

Conformational analysis, molecular structure, spectroscopic, NBO, reactivity descriptors, wavefunction and molecular docking investigations of 5,6-dimethoxy-1-indanone: A potential anti Alzheimer's agent.

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