Computational design of novel flavonoid analogues as potential AChE inhibitors: analysis using group-based QSAR, molecular docking and molecular dynamics simulations

Vats, Chakshu; Dhanjal, Jaspreet Kaur; Goyal, Sukriti; Bharadvaja, Navneeta; Grover, Abhinav

doi:10.1007/s11224-014-0494-3

Cited by 31 publications

(9 citation statements)

References 30 publications

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“…Higher values of F-Test and lower values of standard error of Pred_r 2 se, r 2 _se and q 2 _se indicate a statistically reliable model. Internal and external validation of the model was performed as detailed in our earlier publications [13–16]. …”

Section: Methodsmentioning

confidence: 99%

“…Desmond software was then used to study the molecular dynamics of ligand inside the active site of NA for both H1N1 and H3N2 using the Optimized potentials for liquid simulations 2005 (OLPS) force field [30]. Structures were uploaded in Desmond for further process of molecular dynamics simulations using parameters as mentioned in our earlier publications [16, 31]. The docked complexes were then simulated for 15 ns using above parameters.…”

Section: Methodsmentioning

confidence: 99%

“…Quantitative structure activity relationship (QSAR) is a method of ligand-based drug designing that establishes relationships between structure and inhibitory activity of inhibitors. Group-based QSAR (GQSAR) gives flexibility to traditional QSAR methods by calculating descriptors for the fragment of a molecule rather than calculating descriptors for whole molecule [13–16]. Unlike the traditional QSAR methods, GQSAR can be applied to both congeneric as well as non-congeneric series of compounds.…”

Section: Introductionmentioning

confidence: 99%

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Molecular modeling and lead design of substituted zanamivir derivatives as potent anti-influenza drugs

et al. 2016

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BackgroundInfluenza virus spreads infection by two main surface glycoproteins, namely hemagglutinin (HA) and neuraminidase (NA). NA cleaves the sialic acid receptors eventually releasing newly formed virus particles which then invade new cells. Inhibition of NA could limit the replication of virus to one round which is insufficient to cause the disease.ResultsAn experimentally reported series of acylguanidine zanamivir derivatives was used to develop GQSAR model targeting NA in different strains of influenza virus, H1N1 and H3N2. A combinatorial library was developed and their inhibitory activities were predicted using the GQSAR model.ConclusionThe top leads were analyzed by docking which revealed the binding modes of these inhibitors in the active site of NA (150-loop). The top compound (AMA) was selected for carrying out molecular dynamics simulations for 15 ns which provided insights into the time dependent dynamics of the designed leads. AMA possessed a docking score of −8.26 Kcal/mol with H1N1 strain and −7.00 Kcal/mol with H3N2 strain. Ligand-bound complexes of both H1N1 and H3N2 were observed to be stable for 11 ns and 7 ns respectively. ADME descriptors were also calculated to study the pharmacokinetic properties of AMA which revealed its drug-like properties.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-016-1374-1) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular modeling and lead design of substituted zanamivir derivatives as potent anti-influenza drugs

et al. 2016

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“…Next, Vats et al [117] reported the development of a novel fragment-based or group-based quantitative structure activity relationship (QSAR) model based on 27 flavanoid molecules with known antiacetyl cholinesterase activity. The study is of importance because acetyl cholinesterase is associated with the loss of cholinergic neurons in Alzheimer's disease.…”

Section: Issuementioning

confidence: 99%

Interplay of thermochemistry and Structural Chemistry, the journal (Volume 26, 2015, Issues 1–2) and the discipline

2016

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The contents of issues 1 and 2 of Structural Chemistry from the calendar year 2015 are summarized in the present review. A brief thermochemical commentary and possible guidelines for future research are added to the summary of each paper. Abbreviations AdNDP Adaptive natural density partitioning AIM Atoms in molecules BNNT Boron nitride nanotube CBS Complete basis set DFT Density functional theory HF Hartree-Fock GIAO Gauge-independent atomic orbital HOMO Highest occupied molecular orbital LMO-EDA Localized molecular orbital energy decomposition analysis LUMO Lowest unoccupied molecular orbital MD Molecular dynamics MP2 Second-order Møller-Plesset perturbation NBO Natural bond orbital NMR Nuclear magnetic resonance NT Nanotube ONIOM Our own N-layered integrated molecular orbital and molecular mechanics PCM Polarized continuum model QM/MM Quantum mechanics molecular mechanics QSAR Quantitative structure activity relationship QTAIM Quantum theory of atoms in molecules SAC-CI Symmetry-adapted cluster configuration interaction SAPT Symmetry-adapted perturbation theory SW Stone-Wales TD Time-dependent

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“…Ambure et al utilized molecular docking to build a pharmacophore virtualscreening model that provided new suggestions for designing novel AChE inhibitors [15]. Grover et al studied 27 flavonoid derivatives by 3D-QSAR, molecular docking, and molecular dynamics (MD) simulations, and used the results to create useful guides to designing AChE inhibitors [16]. Correa et al studied 84 N-aryl-monosubstituted derivatives by 3D-QSAR, molecular docking, and molecular dynamics (MD) simulations, which led them to provide helpful advice regarding the design of acetylcholinesterase and butyrylcholinesterase inhibitors [17].…”

Section: Introductionmentioning

confidence: 99%

Combined 3D-QSAR, molecular docking, and molecular dynamics study of tacrine derivatives as potential acetylcholinesterase (AChE) inhibitors of Alzheimer’s disease

Zhou

Wang

et al. 2015

J Mol Model

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Acetylcholinesterase (AChE) is one of the key targets of drugs for treating Alzheimer's disease (AD). Tacrine is an approved drug with AChE-inhibitory activity. In this paper, 3D-QSAR, molecular docking, and molecular dynamics were carried out in order to study 60 tacrine derivatives and their AChE-inhibitory activities. 3D-QSAR modeling resulted in an optimal CoMFA model with q(2) = 0.552 and r(2) = 0.983 and an optimal CoMSIA model with q(2) = 0.581 and r(2) = 0.989. These QSAR models also showed that the steric and H-bond fields of these compounds are important influences on their activities. The interactions between these inhibitors and AChE were further explored through molecular docking and molecular dynamics simulation. A few key residues (Tyr70, Trp84, Tyr121, Trp279, and Phe330) at the binding site of AChE were identified. The results of this study improve our understanding of the mechanisms of AChE inhibitors and afford valuable information that should aid the design of novel potential AChE inhibitors. Graphical Abstract Superposition of backbone atoms of the lowest-energy structure obtained from MD simulation (magenta) onto those of the structure of the initial molecular docking model (green).

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Computational design of novel flavonoid analogues as potential AChE inhibitors: analysis using group-based QSAR, molecular docking and molecular dynamics simulations

Cited by 31 publications

References 30 publications

Molecular modeling and lead design of substituted zanamivir derivatives as potent anti-influenza drugs

Molecular modeling and lead design of substituted zanamivir derivatives as potent anti-influenza drugs

Interplay of thermochemistry and Structural Chemistry, the journal (Volume 26, 2015, Issues 1–2) and the discipline

Combined 3D-QSAR, molecular docking, and molecular dynamics study of tacrine derivatives as potential acetylcholinesterase (AChE) inhibitors of Alzheimer’s disease

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