An Introduction to Density Functional Theory

Bartolotti, Libero J.; Flurchick, K. M.

doi:10.1002/9780470125847.ch4

Cited by 135 publications

(57 citation statements)

References 81 publications

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“…DFT is a successful and promising approach adopted by quantum chemists in the quantum mechanical simulation of periodic systems [41] . There is substantial evidence that DFT provides an accurate description of the electronic and structural properties of small molecules by computing the electronic structure of matter.…”

Section: Density Functional Theorymentioning

confidence: 99%

Pharmacophore-based virtual screening and density functional theory approach to identifying novel butyrylcholinesterase inhibitors

Sakkiah

Lee

2012

Acta Pharmacol Sin

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Aim: To identify the critical chemical features, with reliable geometric constraints, that contributes to the inhibition of butyrylcholinesterase (BChE) function. Methods: Ligand-based pharmacophore modeling was used to identify the critical chemical features of BChE inhibitors. The generated pharmacophore model was validated using various techniques, such as Fischer's randomization method, test set, and decoy set. The best pharmacophore model was used as a query in virtual screening to identify novel scaffolds that inhibit BChE. Compounds selected by the best hypothesis in the virtual screening were tested for drug-like properties, and molecular docking study was applied to determine the optimal orientation of the hit compounds in the BChE active site. To find the reactivity of the hit compounds, frontier orbital analysis was carried out using density functional theory. Results: Based on its correlation coefficient (0.96), root mean square (RMS) deviation (1.01), and total cost (105.72), the quantitative hypothesis Hypo1 consisting of 2 HBA, 1 Hy-Ali, and 1 Hy-Ar was selected as the best hypothesis. Thus, Hypo1 was used as a 3D query in virtual screening of the Maybridge and Chembridge databases. The hit compounds were filtered using ADMET, Lipinski's Rule of Five, and molecular docking to reduce the number of false positive results. Finally, 33 compounds were selected based on their critical interactions with the significant amino acids in BChE's active site. To confirm the inhibitors' potencies, the orbital energies, such as HOMO and LUMO, of the hit compounds and 7 training set compounds were calculated. Among the 33 hit compounds, 10 compounds with the highest HOMO values were selected, and this set was further culled to 5 compounds based on their energy gaps important for stability and energy transfer. From the overall results, 5 hit compounds were confirmed to be potential BChE inhibitors that satisfied all the pharmacophoric features in Hypo1. Conclusion: This study pinpoints important chemical features with geometric constraints that contribute to the inhibition of BChE activity. Five compounds are selected as the best hit BchE-inhibitory compounds.

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Section: Density Functional Theorymentioning

confidence: 99%

Pharmacophore-based virtual screening and density functional theory approach to identifying novel butyrylcholinesterase inhibitors

Sakkiah

Lee

2012

Acta Pharmacol Sin

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“…[12] The combination of the B3LYP method and the 6-31G(d) basis set is know to reproduce geometries in a variety of experimental systems. [17] All compounds, except 16-17, were characterized as minima or maxima on the corresponding potential energy surface (PES) by the frequency calculations. Structure 16-17 was found to be the third order saddle point.…”

Section: Methodsmentioning

confidence: 99%

Experimental and Theoretical Studies of a One‐Flask Synthesis of 3H‐1‐Benzazepines from 2‐Haloanilines and α,β‐Unsaturated Ketones

et al. 2010

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Abstract3H‐1‐Benzazepines are prepared in one step from the reaction of 2‐fluoro‐ or 2‐chloroaniline and several aryl vinyl ketones. Enones 9a–c gave benzazepines 11a–c as expected, showing that alkyl substitution at C4 and C5 in the benzazepines is possible. However, enone 9d underwent decomposition due to conjugate addition of the 2‐fluoroaniline, while enone 10 gave unsaturated imine 12 as the only product able to be isolated. The failure of unsaturated imine 12 to undergo cyclization may indicate that placement of an alkyl group at C3 of the benzazepines may not be possible. Isolation of by‐products buttressed by a computational study verifies a postulated multi‐step process for benzazepine formation: a [1,5] sigmatropic shift in fluoroimine 3, addition elimination to give carbocation 15, formation of the unstable 5H‐1‐benzazepine 7, and acid‐catalyzed isomerization to give the stable 3H‐1‐benzazepine 2. The calculations also indicate why unsaturated imine 12 fails to cyclize. NMR spectroscopic experiments show that the 3H‐benzazepines undergo fast conformational exchange on the NMR time scale at room temperature except when there is an alkyl substituent at C5.

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“…[17,18] The inner layer, the molecular cluster model of the reaction core, was calculated in gas-phase approximation by high level DFT. [19][20][21] The outer layer includes the rest of the protein and the bulk water, so it is very heterogeneous. The QM/SCRF(VS) approach avoids the complications of heterogeneity by considering the protein/water outer layer as a "virtual solvent", a uniform continuum dielectric medium characterized by an empirical parameter, the effective dielectric constant e eff ; 1 e eff 80.…”

Section: Theoretical Analysismentioning

confidence: 99%

Enzyme Isoselective Inhibitors: A Tool for Binding‐Trend Analysis

et al. 2006

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A transition-state analogue inhibitor that covalently reversibly binds to an enzyme formally consists of two parts: the chemical site, CS and the recognition site, RS. We have experimentally and theoretically demonstrated that the trend of binding affinity in a series of isoselective inhibitors (with identical RS and different CS fragments) depends mainly on their CS fragments. Isoselective inhibitors have the same affinity trend toward different enzymes of the same family with a common catalytic mechanism. Thus, very good correlation between experimentally determined and theoretically calculated Ki values was demonstrated. A practical outcome is the application of the described method as a tool for an expert analysis in virtual screening of inhibitor libraries and in the design of new enzyme inhibitors.

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An Introduction to Density Functional Theory

Cited by 135 publications

References 81 publications

Pharmacophore-based virtual screening and density functional theory approach to identifying novel butyrylcholinesterase inhibitors

Pharmacophore-based virtual screening and density functional theory approach to identifying novel butyrylcholinesterase inhibitors

Experimental and Theoretical Studies of a One‐Flask Synthesis of 3H‐1‐Benzazepines from 2‐Haloanilines and α,β‐Unsaturated Ketones

Enzyme Isoselective Inhibitors: A Tool for Binding‐Trend Analysis

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