Description

Publisher details

Elsevier

Publications in this journal

• Probing the simulant behavior of PNPDPP toward parathion and paraoxon: A computational study.

  Authors: Md Abdul Shafeeuulla Khan, Tusar Bandyopadhyay, Bishwajit Ganguly

  Journal of molecular graphics & modelling. 34:10-7.

  The extreme toxicity of organophosphorus nerve agents and pesticides mandates to employ models or simulants in place of the actual compounds in the laboratory. The importance of simulants is known,The extreme toxicity of organophosphorus nerve agents and pesticides mandates to employ models or simulants in place of the actual compounds in the laboratory. The importance of simulants is known, however, their efficacy for direct comparison with the toxic organophosphorus compounds is not well documented. We have examined the potential energy surfaces (PES) for the alkaline hydrolysis of pesticides like paraoxon (diethyl 4-nitrophenyl phosphate), parathion (O,O-diethyl O-4-nitrophenyl phosphorothioate) and PNPDPP (4-nitrophenyl diphenyl phosphate), a simulant with MP2/6-311+G*//B3LYP/6-311+G*+ΔG(solv) (HF/6-31+G*) level of theory. The effect of aqueous solvation was considered with the Integral Equation Formalism Polarizable Continuum Model (IEF-PCM). The alkaline hydrolysis of these organophosphorus compounds reveals that the reaction proceeds through the attack of hydroxide ion at the phosphorus center to form a pentacoordinate intermediate. The calculated free energies of activation for the alkaline hydrolysis of paraoxon and parathion are in good agreement with the available experimental activation free energies. The computed results show that the reaction profiles for the alkaline hydrolysis of paraoxon, parathion and PNPDPP are largely similar; however, the rate of hydrolysis of parathion may be higher than that of paraxon and PNPDPP. Such difference arises due to the less electrophilic nature of the phosphorus atom of parathion molecule as observed in the charge analysis study. The conceptual DFT analysis also showed the similar trend for the alkaline hydrolysis of paraoxon, parathion and PNPDPP with hydroxide anion. This computational study provides a quantitative support toward the use of PNPDPP as a simulant for organophosphorus compounds, which cannot be used directly for the laboratory purposes.

• Energies and physicochemical properties of cation-π interactions in biological structures.

  Authors: Qi-Shi Du, Jian-Zong Meng, Si-Ming Liao, Ri-Bo Huang

  Journal of molecular graphics & modelling. 34:38-45.

  The cation-π interactions occur frequently within or between proteins due to six (Phe, Tyr, Trp, Arg, Lys, and His) of the twenty natural amino acids potentially interacting with metallic cations viaThe cation-π interactions occur frequently within or between proteins due to six (Phe, Tyr, Trp, Arg, Lys, and His) of the twenty natural amino acids potentially interacting with metallic cations via these interactions. In this study, quantum chemical calculations and molecular orbital (MO) theory are used to study the energies and properties of cation-π interactions in biological structures. The cation-π interactions of H(+) and Li(+) are similar to hydrogen bonds and lithium bonds, respectively, in which the small, naked cations H(+) and Li(+) are buried deep within the π-electron density of aromatic molecules, forming stable cation-π bonds that are much stronger than the cation-π interactions of other alkali metal cations. The cation-π interactions of metallic cations with atomic masses greater than that of Li(+) arise mainly from the coordinate bond comprising empty valence atomic orbitals (AOs) of metallic cations and π-MOs of aromatic molecules, though electrostatic interactions may also contribute to the cation-π interaction. The binding strength of cation-π interactions is determined by the charge and types of AOs in the metallic cations. Cation-π interaction energies are distance- and orientation-dependent; energies decrease with the distance (r) and the orientation angle (θ). In solution, the cation-π energies decrease with the increase of the dielectric constant (ɛ) of the solvent; however, solvation has less influence on the H(+)-π and H(3)O(+)-π interactions than on interactions with other cations. The conclusions from this study provide useful theoretical insights into the nature of cation-π interactions and may contribute to the development of better force field parameters for describing the molecular dynamics of cation-π interactions within and between proteins.

• Molecular modeling study on the possible polymers formed during the electropolymerization of 3-hydroxyphenylacetic acid.

  Authors: Deusmaque Carneiro Ferreira, Antonio Eduardo da Hora Machado, Fernanda de Souza Tiago, João Marcos Madurro, Ana Graci Brito Madurro, Odonírio Abrahão

  Journal of molecular graphics & modelling. 34:18-27.

  The compound 3-hydroxyphenylacetic acid (3-HPA) has been used as a monomer in the synthesis of polymeric films by electropolymerization; these films serve as supports for the immobilization ofThe compound 3-hydroxyphenylacetic acid (3-HPA) has been used as a monomer in the synthesis of polymeric films by electropolymerization; these films serve as supports for the immobilization of biomolecules in electrochemical biosensors. To assist in the elucidation of the mechanism of 3-HPA electropolymerization, a systematic quantum mechanical study was conducted. In addition to the monomer, all possible intermediates and the probable oligomers formed during the electropolymerization were investigated using a density functional theory (DFT) method combined with a previous conformational analysis performed with the aid of the RM1 semi-empirical method or a Monte Carlo conformational analysis with the force field OPLS-2005. From the data analysis combined with the experimental results, a mechanism was proposed for the main route of formation of the polymeric films. The mechanism involves the formation of polyethers from the coupling of phenoxide radicals and radicals based on the aromatic ring.

• Exploring the structure requirement for PKCθ inhibitory activity of pyridinecarbonitrile derivatives: an in silico analysis.

  Authors: Yan Li, Ming Hao, Hong Ren, Shuwei Zhang, Xia Wang, Ming Ma, Guohui Li, Ling Yang

  Journal of molecular graphics & modelling. 34:76-88.

  Presently, an in silico modeling was carried out on a large series of 263 PKCθ inhibitors using 3D-QSAR, molecular docking and molecular dynamics (MD) simulations for the first time. Based onPresently, an in silico modeling was carried out on a large series of 263 PKCθ inhibitors using 3D-QSAR, molecular docking and molecular dynamics (MD) simulations for the first time. Based on different alignment rules, several computational models were established with their statistical results compared. The resultant models derived from the database alignment exhibit satisfying internal and external predictive capabilities with q(2) of 0.503, 0.616 and r(2)(pred) of 0.568, 0.602 for CoMFA and CoMSIA, respectively. The consistency of conclusion among 3D contour maps of CoMFA and CoMSIA, molecular docking and molecular dynamics proves the reliability of the developed models. The analysis of the 3D contour plots permits interesting conclusions about the effects of different substituent groups at different positions of the common scaffold. In addition, Leu461 and Asn509 have been identified as the key amino acid residues to form H-bond interaction with the ligand compound. The developed models will provide a clue to the design of novel PKCθ inhibitors.

• The mechanism of copper-catalyzed azide-alkyne cycloaddition reaction: A quantum mechanical investigation.

  Authors: Cihan Ozen, Nurcan Ş Tüzün

  Journal of molecular graphics & modelling. 34:101-7.

  In this study, the mechanism of CuAAC reaction and the structure of copper acetylides have been investigated with quantum mechanical methods, namely B3LYP/6-311+G(d,p). A series of possibleIn this study, the mechanism of CuAAC reaction and the structure of copper acetylides have been investigated with quantum mechanical methods, namely B3LYP/6-311+G(d,p). A series of possible copper-acetylide species which contain up to four copper atoms and solvent molecules as ligand has been evaluated and a four-copper containing copper-acetylide, M1A, was proposed more likely to form based on its thermodynamic stability. The reaction has been modeled with a representative simple alkyne and a simple azide to concentrate solely on the electronic effects of the mechanism. Later, the devised mechanism has been applied to a real system, namely to the reaction of 2-azido-1,1,1-trifluoroethane and ethynylbenzene in the presence of copper. The copper catalyst transforms the concerted uncatalyzed reaction to a stepwise process and lowers the activation barrier. The pre-reactive complexation of the negatively charged secondary nitrogen of azide and the positively charged copper of copper-acetylide brings the azide and the alkyne to a suitable geometry for cycloaddition to take place. The calculated activation barrier difference between the catalyzed and the uncatalyzed reactions is consistent with faster and the regioselective synthesis of triazole product.

• Nonlinear dimensionality reduction and mapping of compound libraries for drug discovery.

  Authors: Michael Reutlinger, Gisbert Schneider

  Journal of molecular graphics & modelling. 34:108-17.

  Visualization of 'chemical space' and compound distributions has received much attraction by medicinal chemists as it may help to intuitively comprehend pharmaceutically relevant molecular features.Visualization of 'chemical space' and compound distributions has received much attraction by medicinal chemists as it may help to intuitively comprehend pharmaceutically relevant molecular features. It has been realized that for meaningful feature extraction from complex multivariate chemical data, such as compound libraries represented by many molecular descriptors, nonlinear projection techniques are required. Recent advances in machine-learning and artificial intelligence have resulted in a transfer of such methods to chemistry. We provide an overview of prominent visualization methods based on nonlinear dimensionality reduction, and highlight applications in drug discovery. Emphasis is on neural network techniques, kernel methods and stochastic embedding approaches, which have been successfully used for ligand-based virtual screening, SAR landscape analysis, combinatorial library design, and screening compound selection.

• Theoretical design and screening of panchromatic phthalocyanine sensitizers derived from TT1 for dye-sensitized solar cells.

  Authors: Linlin Yang, Lianshun Guo, Qianqian Chen, Huafei Sun, Jie Liu, Xianxi Zhang, Xu Pan, Songyuan Dai

  Journal of molecular graphics & modelling. 34:1-9.

  Computational screening of new dyes is becoming an extremely powerful tool, especially when associated with experimental synthetic efforts that might eventually lead to new and more efficientComputational screening of new dyes is becoming an extremely powerful tool, especially when associated with experimental synthetic efforts that might eventually lead to new and more efficient products. Nine novel unsymmetrical zinc phthalocyanine complexes derived from TT1 were designed as sensitizer candidates for dye-sensitized solar cells with three peripheral CH(3), OH, OCH(3), OPh, NH(2), NHCH(3), N(CH(3))(2), NHPh and N(Ph)(2) substituents as the donors and a carboxyl group as the acceptor. The molecular orbital and the electronic absorption spectra properties of these compounds were studied and compared to those of TT1 using the density functional theory and time-dependent density functional theory calculations at B3LYP level with the LANL2DZ basis set. The novel candidates bearing the NH(2), NHCH(3), N(CH(3))(2), NHPh and N(Ph)(2) moieties as the donors were found to be very promising for providing higher efficiencies than that of TT1 or even the current 4.6% efficiency record held by PcS6. They have higher LUMO levels, smaller energy gaps and red-shifted absorption bands compared to those of TT1. The new absorption bands emerging in 450-600nm regions may promote ZnPcLNH(2), ZnPcLNHCH(3), ZnPcLN(CH(3))(2), ZnPcLNHPh and ZnPcLN(Ph)(2) from near infrared to panchromatic sensitizers. Further experimental synthetic efforts are in progress in our group to validate the predictions in this report.

• The harmonic analysis of cylindrically symmetric proteins: A comparison of Dronpa and a DNA sliding clamp.

  Authors: Guang Hu, Servaas Michielssens, Samuel L C Moors, Arnout Ceulemans

  Journal of molecular graphics & modelling. 34:28-37.

  The harmonic analysis of two types of proteins with cylindrical symmetry is performed by the Standard Force Field Normal Mode Analysis and by the elastic network model. For both proteins the globalThe harmonic analysis of two types of proteins with cylindrical symmetry is performed by the Standard Force Field Normal Mode Analysis and by the elastic network model. For both proteins the global elastic modes are assigned to their characteristic topologies. Dronpa is a rigid β-barrel structure, presenting the twisting, bending and breathing motion of a cylindrical rod. The β sliding clamp of Escherichia coli is a hexagonal β-wheel, consisting of rigid segments. In its spectrum four classes of vibrations are identified which are characteristic of an elastic torus. Correlation diagrams and RMSF analysis are compared. The results provide not only a comprehensive validation of the use of both methods to describe the elastic behavior according to the low-frequency normal modes, but also depict the correlated motions of β-barrel and β-wheel proteins. The harmonic flexibility of the Dronpa protein is compared to the principal components of molecular dynamics (MD) simulation. A functionally important localized cleft opening mode is found, which is not detected by harmonic analysis.

• Probing the effect of intermolecular interaction and understanding the electrostatic moments of anacardic acid in the active site of p300 enzyme via DFT and charge density analysis.

  Authors: B Devipriya, P Kumaradhas

  Journal of molecular graphics & modelling. 34:57-66.

  A charge density analysis has been performed on gas phase and docked forms of anacardic acid molecule to understand its charge density distribution, electrostatic moments and the conformation in theA charge density analysis has been performed on gas phase and docked forms of anacardic acid molecule to understand its charge density distribution, electrostatic moments and the conformation in the active site of p300 enzyme. Here, we report the binding affinity of anacardic acid with the p300 enzyme calculated from docking analysis. The charge density distribution of anacardic acid molecule in the gas phase as well as the docked form has been determined from the high level quantum chemical calculations using HF and DFT methods coupled with AIM theory. The charge density study on both forms of anacardic acid differentiates its structural and the electrostatic properties in different environments. When the molecule enters into the active site of p300 its conformation, charge density distribution, dipole moment and electrostatic potential are significantly altered in comparison to its gas phase structure. In the active site, the molecule adopts different conformations, its pentadecyl chain is found to be highly twisted; the charges are redistributed and the dipole moment increases from 2.37 to 3.17D. Due to the charge redistribution, the electronegative region of carboxyl group increased as it is found small in the gas phase. The comparisons between both forms reveal the flexibility of anacardic acid in the active site.

• Theoretical study on the electronic structure and optical properties of carbazole-π-dimesitylborane as bipolar fluorophores for nondoped blue OLEDs.

  Authors: Y Zhang, L L Zhang, R S Wang, X M Pan

  Journal of molecular graphics & modelling. 34:46-56.

  Molecules with D-π-A structures are drawing increased attention for applications in organic electronic devices due to their distinct optoelectronic properties. A study of a new series of bipolarMolecules with D-π-A structures are drawing increased attention for applications in organic electronic devices due to their distinct optoelectronic properties. A study of a new series of bipolar fluorophores that have been chemically modified for use as highly efficient nondoped blue organic light-emitting diodes (OLEDs) has been carried out based on existing molecular structures and a literature survey. The aim of this study is to provide a profound interpretation of the optical and electronic properties and the structure-property relationships of a series of new bipolar fluorophores. The study also aims to predict the photophysical and optoelectronic properties of the new fluorophores. The density functional theory (DFT) has been confirmed as reliable, especially in predicting the properties of unknown products. The geometry and the electronic structure of these molecules in the ground state were studied with DFT and ab initio HF, whereas the lowest singlet excited-state geometries were optimized by ab initio singlet configuration interaction (CIS). The absorption and emission spectra, both in the gas phase and in THF, and the lowest singlet excited energies were calculated by employing the time-dependent density functional theory (TDDFT) and the polarizable continuum model (PCM). To precisely predict the charge-transporting and charge-confining properties of the new fluorophores, three-layered devices have been simulated. The results show that the molecular geometries, HOMOs, LUMOs, energy gaps, ionization potentials (IP), electron affinities (EA), radiative lifetimes (τ), absorption and emission spectra are all tuned by chemical modifications with different π-conjugated bridges. The results also show that these molecular materials could be used as bipolar light-emitting materials for blue and deep-blue OLEDs.

• Virtual screening filters for the design of type II p38 MAP kinase inhibitors: A fragment based library generation approach.

  Authors: Preethi Badrinarayan, G Narahari Sastry

  Journal of molecular graphics & modelling. 34:89-100.

  In this work, we introduce the development and application of a three-step scoring and filtering procedure for the design of type II p38 MAP kinase leads using allosteric fragments extracted fromIn this work, we introduce the development and application of a three-step scoring and filtering procedure for the design of type II p38 MAP kinase leads using allosteric fragments extracted from virtual screening hits. The design of the virtual screening filters is based on a thorough evaluation of docking methods, DFG-loop conformation, binding interactions and chemotype specificity of the 138 p38 MAP kinase inhibitors from Protein Data Bank bound to DFG-in and DFG-out conformations using Glide, GOLD and CDOCKER. A 40ns molecular dynamics simulation with the apo, type I with DFG-in and type II with DFG-out forms was carried out to delineate the effects of structural variations on inhibitor binding. The designed docking-score and sub-structure filters were first tested on a dataset of 249 potent p38 MAP kinase inhibitors from seven diverse series and 18,842 kinase inhibitors from PDB, to gauge their capacity to discriminate between kinase and non-kinase inhibitors and likewise to selectively filter-in target-specific inhibitors. The designed filters were then applied in the virtual screening of a database of ten million (10(7)) compounds resulting in the identification of 100 hits. Based on their binding modes, 98 allosteric fragments were extracted from the hits and a fragment library was generated. New type II p38 MAP kinase leads were designed by tailoring the existing type I ATP site binders with allosteric fragments using a common urea linker. Target specific virtual screening filters can thus be easily developed for other kinases based on this strategy to retrieve target selective compounds.

• Construction of a robust, large-scale, collaborative database for raw data in computational chemistry: the Collaborative Chemistry Database Tool (CCDBT).

  Authors: Mingyang Chen, Amanda C Stott, Shenggang Li, David A Dixon

  Journal of molecular graphics & modelling. 34:67-75.

  A robust metadata database called the Collaborative Chemistry Database Tool (CCDBT) for massive amounts of computational chemistry raw data has been designed and implemented. It performs dataA robust metadata database called the Collaborative Chemistry Database Tool (CCDBT) for massive amounts of computational chemistry raw data has been designed and implemented. It performs data synchronization and simultaneously extracts the metadata. Computational chemistry data in various formats from different computing sources, software packages, and users can be parsed into uniform metadata for storage in a MySQL database. Parsing is performed by a parsing pyramid, including parsers written for different levels of data types and sets created by the parser loader after loading parser engines and configurations.

• The electronic and topological properties of interactions between 1-butyl-3-methylimidazolium hexafluorophosphate/tetrafluoroborate and thiophene.

  Authors: Renqing Lü, Zhanqing Qu, Hong Yu, Fang Wang, Shutao Wang

  Journal of molecular graphics & modelling. 36C:36-41.

  Density functional calculations have been performed to explore the interactions of thiophene and two ionic liquids of 1-butyl-3-methylimidazolium hexafluorophosphate ([BMIM](+)[PF(6)](-)) andDensity functional calculations have been performed to explore the interactions of thiophene and two ionic liquids of 1-butyl-3-methylimidazolium hexafluorophosphate ([BMIM](+)[PF(6)](-)) and 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM](+)[BF(4)](-)). The electronic properties and topological properties of [BMIM](+)[PF(6)](-)-thiophene and [BMIM](+)[BF(4)](-)-thiophene were analyzed. The calculated results reveal that the dominant interactions of C2H2⋯F hydrogen bonds in [BMIM](+)[PF(6)](-) or [BMIM](+)[BF(4)](-) were not destroyed by the thiophene interactions with [BMIM](+)[PF(6)](-) and [BMIM](+)[BF(4)](-). The CH ([BMIM](+))⋯π (thiophene) hydrogen bonds and H(thiophene)⋯F([PF(6)](-) or [BF(4)](-)) hydrogen bonds play crucial roles in the adsorption of thiophene on [BMIM](+)[PF(6)](-) and [BMIM](+)[BF(4)](-).

• Identification of CK2 inhibitors with new scaffolds by a hybrid virtual screening approach based on Bayesian model; pharmacophore hypothesis and molecular docking.

  Authors: Lei Di-Wu, Lin-Li Li, Wen-Jing Wang, Huan-Zhang Xie, Jiao Yang, Chun-Hui Zhang, Qi Huang, Lei Zhong, Shan Feng, Sheng-Yong Yang

  Journal of molecular graphics & modelling. 36C:42-47.

  Protein kinase casein kinase 2 (CK2), a member of the serine/threonine kinase family, has been established as one of the most attractive targets for molecularly targeted cancer therapy. The discoveryProtein kinase casein kinase 2 (CK2), a member of the serine/threonine kinase family, has been established as one of the most attractive targets for molecularly targeted cancer therapy. The discovery of CK2 inhibitors has thus attracted much attention in recent years. In this investigation, a hybrid virtual screening approach based on Bayesian classification model, pharmacophore hypothesis and molecular docking was proposed and employed to identify CK2 inhibitors. We first established a naïve Bayes classification model of CK2 inhibitors/non-inhibitors and pharmacophore hypotheses of CK2 inhibitors. The docking parameters and scoring functions were also optimized in advance. The three virtual screening methods were sequentially used to screen two large chemical libraries, Specs and Enamine, for retrieving new CK2 inhibitors. Finally 30 compounds were selected from the final hits for in vitro CK2 kinase inhibitory assays. Five compounds with completely novel scaffolds showed a good inhibitory potency against CK2, which have good potentials for a future hit-to-lead optimization.

• Monte Carlo simulation of binary surfactant/contaminant/water systems.

  Authors: Zahra Khodadadi, S Morteza Mousavi-Khoshdel, Hussein Gharibi, Seyed Majid Hashemianzadeh, Sohaila Javadian

  Journal of molecular graphics & modelling. 36C:20-29.

  Surfactant-enhanced remediation (SER) is an effective approach for the removal of absorbed hydrophobic organic compounds (HOCs) from contaminated soils. The solubilization of contaminants by mixedSurfactant-enhanced remediation (SER) is an effective approach for the removal of absorbed hydrophobic organic compounds (HOCs) from contaminated soils. The solubilization of contaminants by mixed surfactants with attractive and repulsive head-head interactions was studied by measuring the micelle-water partition coefficient (K(C)) and molar solubilization ratio (MSR) using the lattice Monte Carlo method. The effect of surfactant mixing on the MSR and K(C) of contaminants displayed the following trend: C(4)>C(3)>C(2). Synergistic binary surfactant mixtures showed greater solubilization capacities for contaminants than the corresponding individual surfactants. Mixed micellization parameters, including the interaction parameter β, and activity coefficient f(i), were evaluated with Rubingh's approach. Synergistic mixed-surfactant systems can improve the performance of surfactant-enhanced remediation of soils and groundwater by decreasing the amount of applied surfactant and the cost of remediation.

• Engineered enzyme interactions with polycyclic aromatic hydrocarbons: A theoretical approach.

  Authors: Vito Librando, Matteo Pappalardo

  Journal of molecular graphics & modelling. 36C:30-35.

  In this paper, the techniques of modelling, docking and molecular dynamics were used to study eight single amino acid mutations of the enzyme PhnI to optimise its enzymatic degradation capability.In this paper, the techniques of modelling, docking and molecular dynamics were used to study eight single amino acid mutations of the enzyme PhnI to optimise its enzymatic degradation capability. The eight mutants were first equilibrated to avoid deformations of the secondary and tertiary structure and to minimise alterations in the functionality of the chimera enzymes that were obtained. For this purpose, we monitored the potential energy of the systems and the fluctuations of the backbone of the enzymes. The structures of mutant enzymes, at equilibrium, were subjected to docking calculations with selected PAHs. The results indicated a significant increase in the PAH-enzyme interaction with respect to the wild-type protein. The considerable computing resources offered by the GRID computing system made it possible to perform calculations on the entire enzyme system, consisting of six protein subunits, as highlighted in the recent literature.

• QSPR studies of impact sensitivity of nitro energetic compounds using three-dimensional descriptors.

  Authors: Jie Xu, Ligen Zhu, Dong Fang, Luoxin Wang, Shili Xiao, Li Liu, Weilin Xu

  Journal of molecular graphics & modelling. 36C:10-19.

  The quantitative structure-property relationship (QSPR) studies were performed between molecular structures and impact sensitivity for a diverse set of nitro energetic compounds based onThe quantitative structure-property relationship (QSPR) studies were performed between molecular structures and impact sensitivity for a diverse set of nitro energetic compounds based on three-dimensional (3D) descriptors. The entire set of 156 compounds was divided into a training set of 127 compounds and a test set of 29 compounds according to Kennard and Stones algorithm. Multiple linear regression (MLR) analysis was employed to select the best subset of descriptors and to build linear models; while nonlinear models were developed by means of artificial neural network (ANN). The obtained models with ten descriptors involved show good predictive power for the test set: a squared correlation coefficient (R(2)) of 0.7222 and a standard error of estimation (s) of 0.177 were achieved by the MLR model; while by the ANN model, R(2) and s were 0.8658 and 0.130, respectively. Therefore, the proposed models can be used to predict the impact sensitivity of new nitro compounds for engineering.

• Development of docking-based 3D-QSAR models for PPARgamma full agonists.

  Authors: Laura Guasch, Esther Sala, Cristina Valls, Miquel Mulero, Gerard Pujadas, Santiago Garcia-Vallvé

  Journal of molecular graphics & modelling. 36C:1-9.

  Peroxisome proliferator-activated receptor gamma (PPARγ) has become an attractive molecular target for drugs that aim to treat diabetes mellitus type II, and its therapeutic potency against skinPeroxisome proliferator-activated receptor gamma (PPARγ) has become an attractive molecular target for drugs that aim to treat diabetes mellitus type II, and its therapeutic potency against skin cancer and other skin diseases is also currently being explored. To study the relationship between the structure of several PPARγ full agonists and the trans-activation activity of PPARγ, we have performed a three-dimensional quantitative structure-activity relationship (3D-QSAR) study of tyrosine-based derivatives, based on the 3D alignment of conformations obtained by docking. Highly predictive 3D-QSAR models, with Pearson-R values of 0.86 and 0.90, were obtained for the transactivation activity and binding affinity of PPARγ, respectively. These models are in good agreement with the structural characteristics of the binding pocket of PPARγ and provide some structural insights for the improvement of PPARγ full agonist bioactivities.

• Structure-based 3D-QSAR models and dynamics analysis of novel N-benzyl pyridinone as p38α MAP kinase inhibitors for anticytokine activity.

  Authors: Zaheer Ul-Haq, Waqasuddin Khan, Syeda Rehana Zia, Sadaf Iqbal

  Journal of molecular graphics & modelling. 36C:48-61.

  A novel series of anticytokine N-benzyl pyridinone derivatives that targets p38α MAP kinase has been analyzed by utilizing a combination of molecular modeling techniques. Statistically significantA novel series of anticytokine N-benzyl pyridinone derivatives that targets p38α MAP kinase has been analyzed by utilizing a combination of molecular modeling techniques. Statistically significant structure-based 3D-QSAR models were generated for both CoMFA and CoMSIA, and validated through acceptable predictive ability to support both internal and external set of compounds. Structural changes within the protein key backbone residues (Met109 and Gly110), DFG loop position, and side chain movements (Lys53 and Asn114) as resulted by different substituents on these inhibitors were also examined by molecular dynamics simulation. The protocol applied in this study could be helpful to rationalize potent compounds with better inhibitory activity and selectivity profiles against p38α MAP kinase.

• The adenosine deaminases of Plasmodium vivax and Plasmodium falciparum exhibit surprising differences in ligand specificity.

  Authors: Andrei Ivanov, Ichiro Matsumura

  Journal of molecular graphics & modelling. 35C:43-48.

  Plasmodium vivax and Plasmodium falciparum cause malaria, so proteins essential for their survival in vivo are potential anti-malarial drug targets. Adenosine deaminases (ADA) catalyze thePlasmodium vivax and Plasmodium falciparum cause malaria, so proteins essential for their survival in vivo are potential anti-malarial drug targets. Adenosine deaminases (ADA) catalyze the irreversible conversion of adenosine into inosine, and play a critical role in the purine salvage pathways of Plasmodia and their mammalian hosts. Currently, the number of selective inhibitors of Plasmodium ADAs is limited. One potent and widely used inhibitor of the human ADA (hADA), erythro-9-(2-hydroxy-3-nonly)adenine (EHNA), is a very weak inhibitor (K(i)=120μM) of P. falciparum ADA (pfADA). EHNA-like compounds are thus excluded from consideration as potential inhibitors of Plasmodium ADA in general. However, EHNA activity in P. vivax ADA (pvADA) has not been reported. Here we applied computational molecular modeling to identify ligand recognition mechanisms unique to P. vivax and P. falciparum ADA. Our biochemical experiments show that EHNA is at least 60-fold more potent against pvADA (K(i)=1.9μM) than against pfADA. The D172A pvADA mutant is bound even more tightly (K(i)=0.9μM). These results improve our understanding of the mechanisms of ADA ligand recognition and species-selectivity, and facilitate the rational design of novel EHNA-based ADA inhibitors as anti-malarial drugs. To demonstrate a practical application of our findings we have computationally predicted a novel potential inhibitor of pvADA that will not interact with the human ADA.

• Microsolvation and hydrogen bond interactions in Glycine Dipeptide: Molecular dynamics and density functional theory studies.

  Authors: Balasubramaniam Yogeswari, Ramasamy Kanakaraju, Subramaniam Boopathi, Ponmalai Kolandaivel

  Journal of molecular graphics & modelling. 35C:11-20.

  Molecular dynamics (MD) simulations were carried out to study the conformational characteristics of Glycine Dipeptide (GD) in the presence of explicit water molecules for over 10ns with a MD timeMolecular dynamics (MD) simulations were carried out to study the conformational characteristics of Glycine Dipeptide (GD) in the presence of explicit water molecules for over 10ns with a MD time step of 2fs. The density functional theory (DFT) methods with 6-311G** basis set have been employed to study the effects of microsolvation on the conformations of GD with 5-10 water molecules. The interaction energy with BSSE corrections and the strength of the intermolecular hydrogen bond interactions have been analyzed. The Bader's Atoms in Molecules (AIM) theory has been employed to investigate H-bonding patterns in water interacting complexes. The natural bond orbital (NBO) analysis has been carried out to analyze the charge transfer between proton acceptor to the antibonding orbital of the XH bond in the hydrated complexes. NMR calculations have been carried out at B3LYP/6-311G (2d, 2p) level of theory to analyse the changes in structure and hydrogen bonding environment that occur upon solvation.

• Molecular dynamics simulations of the coenzyme induced conformational changes of Mycobacterium tuberculosisl-alanine dehydrogenase.

  Authors: Baoping Ling, Min Sun, Siwei Bi, Zhihong Jing, Yongjun Liu

  Journal of molecular graphics & modelling. 35C:1-10.

  Mycobacterium tuberculosisl-alanine dehydrogenase (l-MtAlaDH) catalyzes the NADH-dependent reversible oxidative deamination of l-alanine to pyruvate and ammonia. l-MtAlaDH has been proposed to be aMycobacterium tuberculosisl-alanine dehydrogenase (l-MtAlaDH) catalyzes the NADH-dependent reversible oxidative deamination of l-alanine to pyruvate and ammonia. l-MtAlaDH has been proposed to be a potential target in the treatment of tuberculosis. Based on the crystal structures of this enzyme, molecular dynamics simulations were performed to investigate the conformational changes of l-MtAlaDH induced by coenzyme NADH. The results show that the presence of NADH in the binding domain restricts the motions and conformational distributions of l-MtAlaDH. There are two loops (residues 94-99 and 238-251) playing important roles for the binding of NADH, while another loop (residues 267-293) is responsible for the binding of substrate. The opening/closing and twisting motions of two domains are closely related to the conformational changes of l-MtAlaDH induced by NADH.

• TDDFT studies on the structures and ECD spectra of chiral bisarylimidos bearing different lengths of o-alkoxy chain-substituted polyoxomolybdates.

  Authors: Jian-Ping Wang, Li-Kai Yan, Guo-Chun Yang, Wei Guan, Zhong-Min Su

  Journal of molecular graphics & modelling. 35C:49-56.

  The chiroptical properties of bisarylimidos bearing o-alkoxy chain-substituted polyoxomolybdates [Mo(6)O(17)(2,2'-NC(6)H(4)OC(n)H(2n)OC(6)H(4)N)](2-) [n=4(2), 6(3±), 8(4)] were investigated using theThe chiroptical properties of bisarylimidos bearing o-alkoxy chain-substituted polyoxomolybdates [Mo(6)O(17)(2,2'-NC(6)H(4)OC(n)H(2n)OC(6)H(4)N)](2-) [n=4(2), 6(3±), 8(4)] were investigated using the time-dependent density functional method. The results showed that the studied chiral polyoxometalates (POMs) manifested similar absorption sites but displayed different shapes and magnitudes in their electronic circular dichroism (ECD) spectra. The ECD spectra of the studied chiral POMs originated from charge-transfer (CT) transitions from arylimido fragments to the POM cages and from oxygen atoms to the molybdenum atoms in the POM cages. The o-alkoxy chain served as a scaffold for generating chirality rather than contributing to the ECD spectrum of the studied POMs. The induced chiralities of the POM cages were defined by the CT transitions, which were completely localized on the POM cages. Furthermore, the long-range corrected CAM-B3LYP hybrid functional and a basis set that is larger than Lanl2DZ should be used for ECD calculations of chiral POMs. Our work establishes the use of computational studies to investigate the chiroptical properties of chiral POMs and provides theoretical interpretations.

• Binding of GSH conjugates to π-GST: a cross-docking approach.

  Authors: Fabio Lannutti, Alessandro Marrone, Nazzareno Re

  Journal of molecular graphics & modelling. 32:9-18.

  The high degree of flexibility characterizing the members of the GST protein family is supposed to be an evolution-resolved feature related to the detoxifying role of these enzymes. Many evidencesThe high degree of flexibility characterizing the members of the GST protein family is supposed to be an evolution-resolved feature related to the detoxifying role of these enzymes. Many evidences suggest that overexpression of these enzymes may be implicated in the development of acquired resistance to antitumor agents. Among the most effective GST inhibitors, GSH conjugates have been found to be particularly promising because of their low toxicity. Here, we used a cross docking approach based on an ensemble of X-ray structures of GST bound complexes to model the effects of protein flexibility on the binding of GSH conjugates. We showed that our multitarget approach, allows to analyze the impact of protein flexibility and induced fit effects in GSH conjugate docking to GST. Moreover, the inclusion of conserved water molecules in the model allowed to include a further source of target variability and improve the performances in the docking of GSH conjugates through an enhanced description of the GSH moiety interactions. Therefore, a map of ligand-protein interactions reflecting the target variability included in the docking model was retraced and used to gain a thorough insight about the way GSH conjugates bind to GST.

• The structure-property relationship of chiral 1,1'-binaphthyl-based polyoxometalates: TDDFT studies on the static first hyperpolarizabilities and the ECD spectra.

  Authors: Jian-Ping Wang, Li-Kai Yan, Wei Guan, Shi-Zheng Wen, Zhong-Min Su

  Journal of molecular graphics & modelling. 32:1-8.

  In this paper, density functional theory is used to investigate the linear optical and nonlinear optical (NLO) properties of a series of Λ-type chiral compounds composed of two Lindqvist-typeIn this paper, density functional theory is used to investigate the linear optical and nonlinear optical (NLO) properties of a series of Λ-type chiral compounds composed of two Lindqvist-type polyoxometalates (POMs) linked by 1,1'-binaphthyl derivatives through arylimido. It shows that compound 1 which has two POMs on 6-6'-sites of 1,1'-binaphthyl possesses large static first hyperpolarizability and the strongest two-dimensional NLO response among studied compounds. The organic substituents on 2-2'-sites of 1,1'-binaphthyl twofold control the NLO responses of studied compounds. They act as electron acceptors or donors therefore suppress or enhance the NLO responses of studied compounds, and they restrain the torsion angles between two naphthyl rings at certain degrees which are inversely proportional to the NLO responses. Compound 6 with remarkable NLO response is obtained as ferrocene substitutes on 2-2'-sites of 1,1'-binaphthyl. Additionally, the electronic circular dichroism (ECD) spectra of studied compounds are simulated with CAM-B3LYP and B3LYP hybrid functionals. The results agree well with the experimental ECD spectra. The charge-transfer transitions from organic fragment to POM are responsible for the ECD differences between molecular hybrids and their precursors. It is confirmed that these Λ-type chiral compounds are potentially high-dimensional NLO materials and the structure-property relationship of these compounds is presented.

Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.