Comparative Molecular Field Analysis (CoMFA) of MX Compounds using different Semi‐empirical Methods: LUMO Field and its Correlation with Mutagenic Activity

Navajas, Cecil; Poso, Antti; Tuppurainen, Kari; Gynther, Jukka

doi:10.1002/qsar.19960150302

Cited by 19 publications

(14 citation statements)

References 22 publications

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“…Previous CoMFA study indicated that the steric properties of MX analogues with their electron-accepting ability explain their mutagenic activity almost completely [15]. It is also shown that lowest unoccupied molecular orbital (LUMO) energy level is highly correlated with the observed mutagenicity [16]. They comprise an ideal set to test the effect of partial atomic charge variation with quantum mechanics in QSAR studies.…”

Section: Mutagen X and Its Derivatives As An Ideal Set To Test Electrmentioning

confidence: 99%

Large variation in electrostatic contours upon addition of steric parameters and the effect of charge calculation schemes in CoMFA on mutagenicity of MX analogues

Gadhe

Kothandan

Cho

2012

Molecular Simulation

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Section: Mutagen X and Its Derivatives As An Ideal Set To Test Electrmentioning

confidence: 99%

Large variation in electrostatic contours upon addition of steric parameters and the effect of charge calculation schemes in CoMFA on mutagenicity of MX analogues

Gadhe

Kothandan

Cho

2012

Molecular Simulation

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“…As the predictability of a QSAR model is best judged by the external validation using a test set compounds, the data set was divided into training and test sets. Training set included compounds labeled as 1,2,4,6,12,14,15,19,22,24,25,27,31,32, and 34. We adopted multiple validation strategies like LOO cross-validation and external validation.…”

Section: Molecular Electrostatic Potential Calculationsmentioning

confidence: 99%

“…model development A Bayesian model incorporated with 2D descriptors (molecular function class fingerprints of maximum diameter 6 (FCFP_6), AlogP, molecular weight, number of hydrogen bond acceptors, number of hydrogen bond donors, number of rotatable bonds, number of rings, number of aromatic rings, and molecular fractional polar surface area) was generated using DS. For Bayesian model generation, a training set of 15 compounds labeled as 1,2,4,6,12,14,15,19,22,24,25,27,31,32,34 assimilating biological and chemical diversity was developed. The 'Create Bayesian Model' protocol was used for model generation.…”

mentioning

confidence: 99%

Computational Studies of Novel Chymase Inhibitors Against Cardiovascular and Allergic Diseases: Mechanism and Inhibition

Arooj¹,

Thangapandian²,

Strouboulis³

et al. 2012

Chem Biol Drug Des

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To provide a new idea for drug design, a computational investigation is performed on chymase and its novel 1,4-diazepane-2,5-diones inhibitors that explores the crucial molecular features contributing to binding specificity. Molecular docking studies of inhibitors within the active site of chymase were carried out to rationalize the inhibitory properties of these compounds and understand their inhibition mechanism. The density functional theory method was used to optimize molecular structures with the subsequent analysis of highest occupied molecular orbital, lowest unoccupied molecular orbital, and molecular electrostatic potential maps, which revealed that negative potentials near 1,4-diazepane-2,5-diones ring are essential for effective binding of inhibitors at active site of enzyme. The Bayesian model with receiver operating curve statistic of 0.82 also identified arylsulfonyl and aminocarbonyl as the molecular features favoring and not favoring inhibition of chymase, respectively. Moreover, genetic function approximation was applied to construct 3D quantitative structure-activity relationships models. Two models (genetic function approximation model 1 r 2 = 0.812 and genetic function approximation model 2 r 2 = 0.783) performed better in terms of correlation coefficients and crossvalidation analysis. In general, this study is used as example to illustrate how combinational use of 2D ⁄ 3D quantitative structure-activity relationships modeling techniques, molecular docking, frontier molecular orbital density fields (highest occupied molecular orbital and lowest unoccupied molecular orbital), and molecular electrostatic potential analysis may be useful to gain an insight into the binding mechanism between enzyme and its inhibitors.Key words: Bayesian categorization, chymase, genetic function approximation, molecular docking, quantitative structure-activity relationship Abbreviations: ACE, angiotensin-converting enzyme; Ang-I, angiotensin-I; Ang-II, angiotensin-II; DFT, density functional theory; DS, discovery studio; GFA, genetic function approximation; GOLD, genetic optimization for ligand docking; His, histidine; HOMO, highest occupied molecular orbital; LUMO, lowest unoccupied molecular orbital; MESP, molecular electrostatic potential; PDB, protein data bank; Phe, phenylalanine; RMSD, root mean square deviation; SAR, structure-activity relationship; TGF-b, transforming growth factor-b; Trp, tryptophan; Tyr, tyrosine. Received 3 April 2012, revised 30 May 2012 and accepted for publication 4 July 2012Assessing ligand orientation and the strength of ligand…receptor interactions is befitted as an essential component of modern drug discovery and prolific approaches, and programs are available to model ligand at the respective active site. In the course of investigating ligand binding, acquiring the best conformation and orientation of the ligand in the binding pocket along with the accurate estimates (or score) of binding affinities (generally referred to as the 'docking problem') are normally distinguished as t...

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“…For non-steroidal aromatase inhibitors related to fadrozole, Recanatini 6 observed similar models using either the AM1 method for geometry optimization and charge calculations or MAXIMIN2 molecular mechanics for geometry optimization and Gasteiger-Marsili charges. Navajas et al 7 verified that the mutagenic activity of 16 5H-furan-2-one derivatives was correlated with the LUMO field. The MNDO, PM3 and AM1 Hamiltonians were used to optimize and generate the LUMO field.…”

Section: Introductionmentioning

confidence: 95%

The linear relationship between Koopmans' and hydrogen bond energies for some simple carbonyl molecules

Bruns¹,

Haiduke²,

Amaral

2002

J. Braz. Chem. Soc.

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Recentemente Galabov and Bobadova-Parvanova mostraram que a energia de formação da ligação de hidrogênio obtida por cálculo no nível HF/6-31G(d,p) está altamente correlacionada com o potencial eletrostático molecular na região aceptora em alguns compostos carbonílicos simples. Neste trabalho mostramos que o potencial eletrostático pode ser substituído pela energia de Koopmans. A correlação entre esta energia e a energia de formação da ligação de hidrogênio é tão alta quanto aquela observada por Galabov e Bobadova-Parvanova. O potencial de Siegabhn relacionando às energias de Koopmans e cargas GAPT mostra que a energia de ligação de hidrogênio não está simplesmente correlacionada com a carga da região aceptora pois as cargas dos átomos vizinhos são também importantes no processo de ligação de hidrogênio.Recently Galabov and Bobadova-Parvanova have shown that the energy of hydrogen bond formation calculated at the HF/6-31G(d,p) level is highly correlated with the molecular electrostatic potential at the acceptor site for a number of simple carbonyl compounds. Here it is shown that the electrostatic potential can be replaced by Koopmans' energy. The correlation between this energy and the hydrogen bond formation energy is just as high as the one observed by Galabov and Bobadova-Parvanova. The Siegbahn simple potential relating Koopmans' energies and GAPT charges shows that the hydrogen bond energy is not simply correlated with the charge of the acceptor site because the charges on the neighboring atoms are also important in the hydrogen bonding process.

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Comparative Molecular Field Analysis (CoMFA) of MX Compounds using different Semi‐empirical Methods: LUMO Field and its Correlation with Mutagenic Activity

Cited by 19 publications

References 22 publications

Large variation in electrostatic contours upon addition of steric parameters and the effect of charge calculation schemes in CoMFA on mutagenicity of MX analogues

Large variation in electrostatic contours upon addition of steric parameters and the effect of charge calculation schemes in CoMFA on mutagenicity of MX analogues

Computational Studies of Novel Chymase Inhibitors Against Cardiovascular and Allergic Diseases: Mechanism and Inhibition

The linear relationship between Koopmans' and hydrogen bond energies for some simple carbonyl molecules

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