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Showing papers in "Journal of Molecular Modeling in 2007"


Journal ArticleDOI
TL;DR: Modifications that have been made to the NDDO core-core interaction term and to the method of parameter optimization have resulted in a more complete parameter optimization, called PM6, which has, in turn, allowed 70 elements to be parameterized.
Abstract: Several modifications that have been made to the NDDO core-core interaction term and to the method of parameter optimization are described. These changes have resulted in a more complete parameter optimization, called PM6, which has, in turn, allowed 70 elements to be parameterized. The average unsigned error (AUE) between calculated and reference heats of formation for 4,492 species was 8.0 kcal mol−1. For the subset of 1,373 compounds involving only the elements H, C, N, O, F, P, S, Cl, and Br, the PM6 AUE was 4.4 kcal mol−1. The equivalent AUE for other methods were: RM1: 5.0, B3LYP 6–31G*: 5.2, PM5: 5.7, PM3: 6.3, HF 6–31G*: 7.4, and AM1: 10.0 kcal mol−1. Several long-standing faults in AM1 and PM3 have been corrected and significant improvements have been made in the prediction of geometries.

3,018 citations


Journal ArticleDOI
TL;DR: In this paper, the authors carried out a natural bond order B3LYP analysis of the molecules CF(3)X, with X = F, Cl, Br and I. The results showed that the Cl and Br atoms in these molecules closely approximate the [Formula: see text] configuration, where the z-axis is along the R-X bond.
Abstract: Halogen bonding refers to the non-covalent interactions of halogen atoms X in some molecules, RX, with negative sites on others. It can be explained by the presence of a region of positive electrostatic potential, the sigma-hole, on the outermost portion of the halogen's surface, centered on the R-X axis. We have carried out a natural bond order B3LYP analysis of the molecules CF(3)X, with X = F, Cl, Br and I. It shows that the Cl, Br and I atoms in these molecules closely approximate the [Formula: see text] configuration, where the z-axis is along the R-X bond. The three unshared pairs of electrons produce a belt of negative electrostatic potential around the central part of X, leaving the outermost region positive, the sigma-hole. This is not found in the case of fluorine, for which the combination of its high electronegativity plus significant sp-hybridization causes an influx of electronic charge that neutralizes the sigma-hole. These factors become progressively less important in proceeding to Cl, Br and I, and their effects are also counteracted by the presence of electron-withdrawing substituents in the remainder of the molecule. Thus a sigma-hole is observed for the Cl in CF(3)Cl, but not in CH(3)Cl.

1,893 citations


Journal ArticleDOI
TL;DR: An explanation for its occurrence in terms of a region of positive electrostatic potential present on the outermost portions of some covalently-bonded halogen atoms is presented.
Abstract: Halogen bonding (XB) is a type of noncovalent interaction between a halogen atom X in one molecule and a negative site in another. X can be chlorine, bromine or iodine. The strength of the interaction increases in the order Cl

1,241 citations


Journal ArticleDOI
TL;DR: In this paper, the σ-hole concept and the outer regions of positive electrostatic potential on the outer surfaces of divalently-bonded Group VI atoms were used to explain the noncovalent but highly directional interactions with nucleophiles.
Abstract: It has been observed both experimentally and computationally that some divalently-bonded Group VI atoms interact in a noncovalent but highly directional manner with nucleophiles We show that this can readily be explained in terms of regions of positive electrostatic potential on the outer surfaces of such atoms, these regions being located along the extensions of their existing covalent bonds These positive regions can interact attractively with the lone pairs of nucleophiles The existence of such a positive region is attributed to the presence of a “σ-hole” This term designates the electron-deficient outer lobe of a half-filled p bonding orbital on the Group VI atom The positive regions become stronger as the electronegativity of the atom decreases and its polarizability increases, and as the groups to which it is covalently bonded become more electron-withdrawing We demonstrate computationally that the σ-hole concept and the outer regions of positive electrostatic potential account for the existence, directionalities and strengths of the observed noncovalent interactions

443 citations


Journal ArticleDOI
TL;DR: Results of NOCV analysis, compared with Mulliken populations analysis and Zigler–Rauk interaction–energy decomposition, demonstrate that the use of the natural valence orbitals allows for a separation of the σ-donation and π-back-donations contributions to the ligand–fragment bond.
Abstract: Natural orbitals for chemical valence (NOCV) are defined as the eigenvectors of the chemical valence operator defined by Nalewajski et al.; they decompose the deformation density (differential density, Deltarho) into diagonal contributions. NOCV were used in a description of the chemical bond between the organometallic fragment and the ligand in example transition-metal complexes: heme-CO ([FeN(5)C(20)H(15)]-CO), [Ni-diimine hydride]-ethylene ([N;N-Ni-H]-C(2)H(4), N;N = -NH-CH-CH-NH-), and [Ni(NH(3))(3)]-CO. DFT calculations were performed using gradient-corrected density functional theory (DFT) in the fragments resolution, using the fragment/ligand Kohn-Sham orbitals as a basis set in calculations for the whole fragment-ligand complex. It has been found that NOCV lead to a very compact description of the fragment-ligand bond, with only a few orbitals exhibiting non-zero eigenvalues. Results of NOCV analysis, compared with Mulliken populations analysis and Zigler-Rauk interaction-energy decomposition, demonstrate that the use of the natural valence orbitals allows for a separation of the sigma-donation and pi-back-donation contributions to the ligand-fragment bond. They can be also useful in comparison of these contributions in different complexes.

440 citations


Journal ArticleDOI
TL;DR: Computational evidence is provided that fluorine does have the capability of forming halogen bonds, if R is sufficiently electron withdrawing, and it is shown how the computed electrostatic potentials can provide guidance in selecting appropriate halide/base pairs.
Abstract: In some halides RX, the halogen X has a region of positive electrostatic potential on its outermost portion, centered around the extension of the R−X bond. The electrostatic attraction between this positive region and a lone pair of a Lewis base is termed halogen bonding. The existence and magnitudes of such positive potentials on some covalently bonded halogens, and the characteristic directionality of the interaction, can be explained in terms of the degree of sp hybridization and polarizability of X and the electronegativity of R. Halogen bonding increases in strength in the order Cl < Br < I; fluorine is frequently said to not form halogen bonds, although a notable result of the present study is computational evidence that it does have the capability of doing so, if R is sufficiently electron withdrawing. An increasingly important application of halogen bonding is in the design of new materials (e.g., crystal engineering). In this paper, we present the calculated energies of a series of halogen-bonding interactions that could be the basis for forming linear chains, of types X----X----X---- or X----Y----X----Y----. We focus upon chlorides and bromides, and nitrogen bases. The B3PW91/6-311G(3df,2p) and MP2/6-311++G(3df,2p) procedures were used. We show how the computed electrostatic potentials (B3PW91/6-31G**) can provide guidance in selecting appropriate halide/base pairs.

325 citations


Journal ArticleDOI
TL;DR: It is shown that classical electrostatic interactions determine the shape and depth of the π-π stacking potential energy surface and a similarly good performance is achieved with the computationally very robust and efficient local density approximation (LDA).
Abstract: Through comparison with ab initio reference data, we have evaluated the performance of various density functionals for describing π-π interactions as a function of the geometry between two stacked benzenes or benzene analogs, between two stacked DNA bases, and between two stacked Watson–Crick pairs. Our main purpose is to find a robust and computationally efficient density functional to be used specifically and only for describing π-π stacking interactions in DNA and other biological molecules in the framework of our recently developed QM/QM approach "QUILD". In line with previous studies, most standard density functionals recover, at best, only part of the favorable stacking interactions. An exception is the new KT1 functional, which correctly yields bound π-stacked structures. Surprisingly, a similarly good performance is achieved with the computationally very robust and efficient local density approximation (LDA). Furthermore, we show that classical electrostatic interactions determine the shape and depth of the π-π stacking potential energy surface.

121 citations


Journal ArticleDOI
TL;DR: Nafion, whose side-chain length is intermediate of the three polymers studied, is found to have the most mobile polymer side-chains at the higher level of hydration, suggesting that there could be an optimal side- chain length in these systems.
Abstract: The Nafion, Dow and Aciplex systems – where the prime differences lies in the side-chain length – have been studied by molecular dynamics (MD) simulation under standard pressure and temperature conditions for two different levels of hydration: 5 and 15 water molecules per (H)SO3 end-group. Structural features such as water clustering, water-channel dimensions and topology, and the dynamics of the hydronium ions and water molecules have all been analysed in relation to the dynamical properties of the polymer backbone and side-chains. It is generally found that mobility is promoted by a high water content, with the side-chains participating actively in the H3O+/H2O transport mechanism. Nafion, whose side-chain length is intermediate of the three polymers studied, is found to have the most mobile polymer side-chains at the higher level of hydration, suggesting that there could be an optimal side-chain length in these systems. There are also some indications that the water-channel network connectivity is optimal for high water-content Nafion system, and that this could explain why Nafion appears to exhibit the most favourable overall hydronium/water mobility.

112 citations


Journal ArticleDOI
TL;DR: It is shown that polyhalogenated alkanes and ethers, which include the most powerful known anesthetics, have strong positive potentials, VS,max, associated with their hydrogens, chlorines and bromines (but not fluorines).
Abstract: General anesthetics apparently act through weak, noncovalent and reversible interactions with certain sites in appropriate brain proteins. As a means of gaining insight into the factors underlying anesthetic potency, we have analyzed the computed electrostatic potentials V S(r) on the surfaces of 20 molecules with activities that vary between zero and high. Our results are fully consistent with, and help to interpret, what has been observed experimentally. We find that an intermediate level of internal charge separation is required; this is measured by Π, the average absolute deviation of V S(r), and the approximate window is 7 < Π < 13 kcal mol−1. This fits in well with the fact that anesthetics need to be lipid soluble, but also to have some degree of hydrophilicity. We further show that polyhalogenated alkanes and ethers, which include the most powerful known anesthetics, have strong positive potentials, V S,max, associated with their hydrogens, chlorines and bromines (but not fluorines). These positive sites may impede the functioning of key brain proteins, for example by disrupting their normal hydrogen-bond patterns. It has indeed been recognized for some time that the most active polyhalogenated alkanes and ethers contain hydrogens usually in combination with chlorines and/or bromines.

59 citations


Journal ArticleDOI
TL;DR: The mode of bonding affects stability and reactivity of molecule on the frame of nonrelativistic limit of the rigged quantum electrodynamics using new indices for description of bond properties related to bond orders have been characterized here.
Abstract: How the mode of bonding affects stability and reactivity of molecule on the frame of nonrelativistic limit of the rigged quantum electrodynamics using new indices for description of bond properties related to bond orders have been characterized here. These indices are in close relation with tensorial interpretation of bond that among others allows discriminating covalent bonds using spindle structure concept. The real three-dimensional space representation of new interaction energy density utilized in this study contribute to better understanding of interaction phenomena between atoms and molecules. The differences in reactivity and stabilities of molecules have their root in the redistribution of interaction energy density.

52 citations


Journal ArticleDOI
TL;DR: A model of H5N1 NS1 was developed by homology modeling, molecular mechanics and molecular dynamics simulations, and it was found that the D92E mutation could result in weakened interactions of the carboxylate side chain with other phosphorylated residues, thereby activating phosphorylation of NS1.
Abstract: Virulent H5N1 strains of influenza virus often harbor a D92E point mutation in the nonstructural protein NS1. This crucial mutation has been correlated with increased virulence and/or cytokine resistance, but the structural implications of such a change are still unclear. Furthermore, NS1 protein could also be a potential target for the development of novel antiviral agents against H5N1 strains. Therefore, a reasonable 3D model of H5N1 NS1 is important for the understanding of the molecular basis of increased virulence and the design of novel antiviral agents. Based on the crystal structure of a non-H5N1 NS1 protein, a model of H5N1 NS1 was developed by homology modeling, molecular mechanics and molecular dynamics simulations. It was found that the D92E mutation could result in weakened interactions of the carboxylate side chain with other phosphorylated residues, thereby activating phosphorylation of NS1.

Journal ArticleDOI
TL;DR: A fully automated method to predict interacting amino acid residues on protein surfaces of monomeric 3D structures, and a cluster algorithm to locate surface exposed areas with high interface propensities, is developed and tested.
Abstract: We have developed a fully automated method, InterProSurf, to predict interacting amino acid residues on protein surfaces of monomeric 3D structures. Potential interacting residues are predicted based on solvent accessible surface areas, a new scale for interface propensities, and a cluster algorithm to locate surface exposed areas with high interface propensities. Previous studies have shown the importance of hydrophobic residues and specific charge distribution as characteristics for interfaces. Here we show differences in interface and surface regions of all physical chemical properties of residues as represented by five quantitative descriptors. In the current study a set of 72 protein complexes with known 3D structures were analyzed to obtain interface propensities of residues, and to find differences in the distribution of five quantitative descriptors for amino acid residues. We also investigated spatial pair correlations of solvent accessible residues in interface and surface areas, and compared log-odds ratios for interface and surface areas. A new scoring method to predict potential functional sites on the protein surface was developed and tested for a new dataset of 21 protein complexes, which were not included in the original training dataset. Empirically we found that the algorithm achieves a good balance in the accuracy of precision and sensitivity by selecting the top eight highest scoring clusters as interface regions. The performance of the method is illustrated for a dimeric ATPase of the hyperthermophile, Methanococcus jannaschii, and the capsid protein of Human Hepatitis B virus. An automated version of the method can be accessed from our web server at http://curie.utmb.edu/prosurf.html.

Journal ArticleDOI
TL;DR: A new Density Functional Theory chemistry model called CHIH-DFT (Chihuahua-Heterocycles-Density functional Theory) is used that reflects the mixture of Hartree Fock exchange and DFT exchange according to a mixing parameter based on empirical rules suited for heterocyclic systems to calculate the molecular structure of these antitubercular compounds.
Abstract: Three of the most frequent antitubercular agents employed against Mycobacterium tuberculosis are: Rifampicin, Isoniazid and Pyrazinamide. It has been proven that the use of these antitubercular agents together, shortens the treatment period from 12–18 months to 6 months [1]. In this work we use a new Density Functional Theory chemistry model called CHIH-DFT (Chihuahua-Heterocycles-Density Functional Theory) that reflects the mixture of Hartree Fock exchange and DFT exchange, according to a mixing parameter based on empirical rules suited for heterocyclic systems. This new chemistry model was used to calculate the molecular structure of these antitubercular compounds, as well as their infrared, UV spectra, chemical reactivity and electronic properties. The UV and infrared spectra were obtained by experimental techniques. The calculated molecular structure, UV and IR spectra values from CHIH-DFT were compared with experimentally obtained values and theoretical studies. These results are in good agreement with experimental and theoretical studies. We also predicted using the relative electrophilicity and relative nucleophilicity concepts as defined by Roy et al. [2] the chemical active sites for the three antitubercular compounds as well as their electronegativity, ionization potential, electron affinity, hardness, dipole moment, EHOMO-ELUMO gap energy, etc.

Journal ArticleDOI
Philippe Ferrara1, Edgar Jacoby1
TL;DR: An assessment of the utility of homology models in HTD by docking 300,000 anticipated inactive compounds along with 642 known actives into the binding site of the insulin-like growth factor 1 receptor (IGF-1R) kinase constructed by homology modeling.
Abstract: High throughput docking (HTD) is routinely used for in silico screening of compound libraries with the aim to find novel leads in a drug discovery program. In the absence of an experimentally determined structure, a homology model can be used instead. Here we present an assessment of the utility of homology models in HTD by docking 300,000 anticipated inactive compounds along with 642 known actives into the binding site of the insulin-like growth factor 1 receptor (IGF-1R) kinase constructed by homology modeling. Twenty-one different templates were selected and the enrichment curves obtained by the homology models were compared to those obtained by three IGF-1R crystal structures. The results show a wide range of enrichments from random to as good as two of the three IGF-1R crystal structures. Nevertheless, if we consider the enrichment obtained at 2% of the database screened as a performance criterion, the best crystal structure outperforms the best homology model. Surprisingly, the sequence identity of the template to the target is not a good descriptor to predict the enrichment obtained by a homology model. The three homology models that yield the worst enrichment have the smallest binding-site volume. Based on our results, we propose ensemble docking to perform HTD with homology models.

Journal ArticleDOI
TL;DR: Effective force fields for Ni-C interactions developed by Yamaguchi and Maruyama for the formation of metallofullerenes are modified to simulate the catalyzed growth of single-wall carbon nanotubes on Nin clusters with n >20.
Abstract: Effective force fields for Ni-C interactions developed by Yamaguchi and Maruyama for the formation of metallofullerenes are modified to simulate the catalyzed growth of single-wall carbon nanotubes on Ni(n) clusters with n >20, and the reactive empirical bond order Brenner potential for C-C interactions is also revised to include the effect of the metal atoms on such interactions.

Journal ArticleDOI
TL;DR: The results of a study using molecular dynamics simulations performed for five pairs of enzymes indicate that protein dynamics play an important role in catalytic processes where structural rearrangements, such as those required for active site access by substrate, are involved and support the notion that cold adaptation may have evolved by selective changes in regions of enzyme structure rather than in global change to the whole protein.
Abstract: Enzymes from cold-adapted species are significantly more active at low temperatures, even those close to zero Celsius, but the rationale of this adaptation is complex and relatively poorly understood. It is commonly stated that there is a relationship between the flexibility of an enzyme and its catalytic activity at low temperature. This paper gives the results of a study using molecular dynamics simulations performed for five pairs of enzymes, each pair comprising a cold-active enzyme plus its mesophilic or thermophilic counterpart. The enzyme pairs included alpha-amylase, citrate synthase, malate dehydrogenase, alkaline protease and xylanase. Numerous sites with elevated flexibility were observed in all enzymes; however, differences in flexibilities were not striking. Nevertheless, amino acid residues common in both enzymes of a pair (not present in insertions of a structure alignment) are generally more flexible in the cold-active enzymes. The further application of principle component analysis to the protein dynamics revealed that there are differences in the rate and/or extent of opening and closing of the active sites. The results indicate that protein dynamics play an important role in catalytic processes where structural rearrangements, such as those required for active site access by substrate, are involved. They also support the notion that cold adaptation may have evolved by selective changes in regions of enzyme structure rather than in global change to the whole protein.

Journal ArticleDOI
TL;DR: The first computational study of the clinically relevant E35D mutation of HIV-1 protease in its unbound conformation and complexed with the clinical inhibitor amprenavir and a sample substrate is reported, giving a plausible explanation for its ability to increase the level of resistance.
Abstract: Drug resistance is a very important factor contributing to the failure of current HIV therapies. The ability to understand the resistance mechanism of HIV-protease mutants may be useful in developing more effective and longer lasting treatment regimens. In this paper, we report the first computational study of the clinically relevant E35D mutation of HIV-1 protease in its unbound conformation and complexed with the clinical inhibitor amprenavir and a sample substrate (Thr-Ile-Met-Met-Gln-Arg). Our data, collected from 10 ns molecular-dynamics simulations, show that the E35D mutation results in an increased flexibility of the flaps, thereby affecting the conformational equilibrium between the closed and semi-open conformations of the free protease. The E35D mutation also causes a significant reduction of the calculated binding free energies both for substrate and amprenavir, thus giving a plausible explanation for its ability to increase the level of resistance. One possible explanation for the emergence of this mutation, despite its unfavorable effect on substrate affinity, might be the role of E35D as an escape mutation, which favors escape from the immune system in addition to conferring drug resistance.

Journal ArticleDOI
TL;DR: 3D-QSAR analysis of several DPP-IV inhibitors, which were aligned by the receptor-based technique, are reported, which are robust with statistically significant r2, q2, and r2-q2 values.
Abstract: Dipeptidyl peptidase IV (DPP-IV) deactivates the incretin hormones GLP-1 and GIP by cleaving the penultimate proline or alanine from the N-terminal (P1-position) of the peptide. Inhibition of this enzyme will prevent the degradation of the incretin hormones and maintain glucose homeostasis; this makes it an attractive target for the development of drugs for diabetes. This paper reports 3D-QSAR analysis of several DPP-IV inhibitors, which were aligned by the receptor-based technique. The conformation of the molecules in the active site was obtained through docking methods. The QSAR models were generated on two training sets composed of 74 and 25 molecules which included phenylalanine, thiazolidine, and fluorinated pyrrolidine analogs. The 3D-QSAR models are robust with statistically significant r(2), q(2), and r(pred)(2) values. The CoMFA and CoMSIA models were used to design some new inhibitors with several fold higher binding affinity.

Journal ArticleDOI
TL;DR: This study suggests that introduction of bulky and highly electronegative groups on the basic amino side chain along with decreasing steric bulk and electr onegativity on the phenanthrene ring might be suitable for designing better antitubercular agents.
Abstract: AbstractComparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) based on three-dimensional quantitative structure–activity relationship (3D-QSAR) studies were conducted on a series (44 compounds) of diaryloxy-methano-phenanthrene derivatives as potent antitubercular agents. The best predictions were obtained with a CoMFA standard model (q2=0.625, r2=0.994) and with CoMSIA combined steric, electrostatic, and hydrophobic fields (q2=0.486, r2=0.986). Both models were validated by a test set of seven compounds and gave satisfactory predictive r2 values of 0.999 and 0.745, respectively. CoMFA and CoMSIA contour maps were used to analyze the structural features of the ligands to account for the activity in terms of positively contributing physicochemical properties: steric, electrostatic, and hydrophobic fields. The information obtained from CoMFA and CoMSIA 3-D contour maps can be used for further design of phenanthrene-based analogs as anti-TB agents. The resulting contour maps, produced by the best CoMFA and CoMSIA models, were used to identify the structural features relevant to the biological activity in this series of analogs. Further analysis of these interaction-field contour maps also showed a high level of internal consistency. This study suggests that introduction of bulky and highly electronegative groups on the basic amino side chain along with decreasing steric bulk and electronegativity on the phenanthrene ring might be suitable for designing better antitubercular agents.

Journal ArticleDOI
TL;DR: The results of 60 ns molecular dynamics simulations of dioxygen diffusion inside Cyg matrix are discussed and a comparison of gaseous ligand transport in Cyg and in the most studied heme protein myoglobin is presented.
Abstract: Cytoglobin (Cyg)—a new member of the vertebrate heme globin family—is expressed in many tissues of the human body but its physiological role is still unclear It may deliver oxygen under hypoxia, serve as a scavenger of reactive species or be involved in collagen synthesis This protein is usually six-coordinated and binds oxygen by a displacement of the distal HisE7 imidazole In this paper, the results of 60 ns molecular dynamics (MD) simulations of dioxygen diffusion inside Cyg matrix are discussed In addition to a classical MD trajectory, an approximate Locally Enhanced Sampling (LES) method has been employed Classical diffusion paths were carefully analyzed, five cavities in dynamical structures were determined and at least four distinct ligand exit paths were identified The most probable exit/entry path is connected with a large tunnel present in Cyg Several residues that are perhaps critical for kinetics of small gaseous diffusion were discovered A comparison of gaseous ligand transport in Cyg and in the most studied heme protein myoglobin is presented Implications of efficient oxygen transport found in Cyg to its possible physiological role are discussed

Journal ArticleDOI
TL;DR: The structure and stability of endohedral X@C20F20 complexes have been computed at the B3LYP level of theory and, on the basis of the computed nucleus independent chemical shift values at the cage center, both C20f20 and C20F 20 are aromatic.
Abstract: The structure and stability of endohedral X@C20F20 complexes (X = H−, F−, Cl−, Br−, H, He) have been computed at the B3LYP level of theory. All complexes in I h symmetry were found to be energy minimum structures. H−@C20F20 and F−@C20F20 complexes have negative inclusion energies, while other complexes have positive inclusion energies. Similarity between C20F20 and C20H20 has been found for X = H and He. On the basis of the computed nucleus independent chemical shift values at the cage center, both C20F20 and C20F20 are aromatic.

Journal ArticleDOI
TL;DR: The structure of the proposed catalytic sites are shown to be dependent on electrostatic and structural relaxation processes occurring at the surfaces of the precursor material, and how these effects may be adequately captured by small molecular models of the active sites is shown.
Abstract: Realistic molecular models of one and two-centre catalytic active sites originating from the cleavage of a precursor material known to give rise to an active double metal cyanide catalyst are described. Via periodic density functional calculations the structure of the proposed catalytic sites are shown to be dependent on electrostatic and structural relaxation processes occurring at the surfaces of the precursor material. It is shown how these effects may be adequately captured by small molecular models of the active sites. The general methodology proposed should provide a computationally efficient basis for detailed future studies into catalytic reactions over double metal cyanide materials.

Journal ArticleDOI
TL;DR: The extension of the AM1 semiempirical molecular orbital technique, AM1*, has been parameterized for the elements Cu and Zn, and parameters are now available for H, C, N, O and F.
Abstract: Our extension of the AM1 semiempirical molecular orbital technique, AM1*, has been parameterized for the elements Cu and Zn. The basis sets for both metals contain a set of d-orbitals. The zinc parameterization uses a filled d-shell to give 12 valence electrons. Thus, AM1* parameters are now available for H, C, N, O and F (which use the original AM1 parameters), Al, Si, P, S, Cl, Ti, Cu, Zn, Zr and Mo. The performance and typical errors of AM1* are discussed for the newly parameterized elements.

Journal ArticleDOI
TL;DR: This work has aligned the sequences of 29 ORs for which ligand binding data are available and provides a rationale for amino acids in equivalent positions in most of the odorant receptors considered and helps to identify other amino acids that could be important for ligandbinding.
Abstract: Odorant receptors belong to class A of the G protein-coupled receptors (GPCRs) and detect a large number of structurally diverse odorant molecules. A recent structural bioinformatic analysis suggests that structural features are conserved across class A of GPCRs in spite of their low sequence identity. Based on this work, we have aligned the sequences of 29 ORs for which ligand binding data are available. Recent site-directed mutagenesis experiments on one such receptor (MOR174-9) provide information that helped to identify nine amino-acid residues involved in ligand binding. Our modeling provides a rationale for amino acids in equivalent positions in most of the odorant receptors considered and helps to identify other amino acids that could be important for ligand binding. Our findings are consistent with most of the previous models and allow predictions for site-directed mutagenesis experiments, which could also validate our model.

Journal ArticleDOI
TL;DR: Contour plots generated for the CoMFA and CoMSIA models reveal useful clues for improving the activity of mPGES-1 inhibitors, and substitutions of an electronegative fluorine atom or a bulky hydrophilic phenoxy group at the meta or para positions of the biphenyl rings might improve inhibitory activity.
Abstract: Microsomal prostaglandin E2 synthase (mPGES-1) has been identified recently as a novel target for treating pain and inflammation. The aim of this study is to understand the binding affinities of reported inhibitors for mPGES-1 and further to design potential new mPGES-1 inhibitors. 3D-QSAR-CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity indices analysis) - techniques were employed on a series of indole derivatives that act as selective mPGES-1 inhibitors. The lowest energy conformer of the most active compound obtained from systematic conformational search was used as a template for the alignment of 32 compounds. The models obtained were used to predict the activities of the test set of eight compounds, and the predicted values were in good agreement with the experimental results. The 3D-QSAR models derived from the training set of 24 compounds were all statistically significant (CoMFA; q 2 = 0.89, r 2 = 0.95, $$ r^{{\text{2}}}_{{{\text{bs}}}} = 0.98 $$ , $$ r^{{\text{2}}}_{{{\text{pred}}}} = 0.83 $$ and CoMSIA; q 2 = 0.84, r 2 = 0.93, $$ r^{{\text{2}}}_{{{\text{bs}}}} = 0.93 $$ , $$ r^{{\text{2}}}_{{{\text{pred}}}} = 0.94 $$ ). Contour plots generated for the CoMFA and CoMSIA models reveal useful clues for improving the activity of mPGES-1 inhibitors. In particular, substitutions of an electronegative fluorine atom or a bulky hydrophilic phenoxy group at the meta or para positions of the biphenyl rings might improve inhibitory activity. A plausible binding mode between the ligands and mPGES-1 is also proposed.

Journal ArticleDOI
TL;DR: The results indicate that the subsystem-based methods provide an interesting alternative to that based on the Kohn-Sham equations and leads to a computational approach comparing favorably with more than twenty methods based onThe Kohn -Sham equations including the ones, which use extensively empirical parameterizations.
Abstract: Interaction energies for a representative sample of 39 intermolecular complexes are calculated using two computational approaches based on the subsystem formulation of density functional theory introduced by Cortona (Phys. Rev. B 44:8454, 1991), adopted for studies of intermolecular complexes (Wesolowski and Weber in Chem. Phys. Lett. 248:71, 1996). The energy components (exchange-correlation and non-additive kinetic) expressed as explicit density functionals are approximated by means of gradient-free- (local density approximation) of gradient-dependent- (generalized gradient approximation) approximations. The sample of the considered intermolecular complexes was used previously by Zhao and Truhlar to compare the interaction energies derived using various methods based on the Kohn-Sham equations with high-level quantum chemistry results considered as the reference. It stretches from rare gas dimers up to strong hydrogen bonds. Our results indicate that the subsystem-based methods provide an interesting alternative to that based on the Kohn-Sham equations. Local density approximation, which is the simplest approximation for the relevant density functionals and which does not rely on any empirical data, leads to a computational approach comparing favorably with more than twenty methods based on the Kohn-Sham equations including the ones, which use extensively empirical parameterizations. For various types of non-bonding interactions, the strengths and weaknesses of gradient-free and gradient-dependent approximations to exchange-correlation and non-additive kinetic energy density functionals are discussed in detail.

Journal ArticleDOI
TL;DR: The structure of Zn4Al2 Layered Double Hydroxide intercalated with benzencarboxylate (C6H5COO−) was solved using molecular modeling combined with experiment and good agreement has been achieved between calculated and measured basal spacing.
Abstract: The structure of Zn4Al2 Layered Double Hydroxide intercalated with benzencarboxylate (C6H5COO−) was solved using molecular modeling combined with experiment (X-ray powder diffraction, IR spectroscopy, TG measurements). Molecular modeling revealed the arrangement of guest molecules, layer stacking, water content and water location in the interlayer space of the host structure. Molecular modeling using empirical force field was carried out in Cerius2 modeling environment. Results of modeling were confronted with experiment that means comparing the calculated and measured diffraction pattern and comparing the calculated water content with the thermogravimetric value. Good agreement has been achieved between calculated and measured basal spacing: d calc = 15.3 A and d exp = 15.5 A. The number of water molecules per formula unit (6H2O per Zn4Al2(OH)12) obtained by modeling (i.e., corresponding to the energy minimum) agrees with the water content estimated by thermogravimetry. The long axis of guest molecules are almost perpendicular to the LDH layers, anchored to the host layers via COO− groups. Mutual orientation of benzoate ring planes in the interlayer space keeps the parquet arrangement. Water molecules are roughly arranged in planes adjacent to host layers together with COO− groups.

Journal ArticleDOI
TL;DR: Molecular docking studies on 24 camptothecin-like inhibitors present in the NCI Anti-cancer Agents Mechanism Database allowed us to analyze some conformations adopted by the inhibitors during active site binding, confirming the role of hydrogen bond and contributed to clarify the loss of activity due to single point mutations.
Abstract: Topoisomerase I (Top1) is an essential enzyme participating to all those processes associated with separation of DNA strands It manages superhelical tensions through the transient breakage of one strand of duplex DNA, followed by the unwinding of supercoiled DNA Camptothecins, a class of alkaloids extracted from the wood of a Chinese tree, were found to be potent inhibitors of Topoisomerase I The National Cancer Institute (NCI) Anti-cancer Agents Mechanism Database contains several camptothecins derivatives, classified as selective Top1 inhibitors In this work we performed molecular docking studies on 24 camptothecin-like inhibitors present in this database (using Autodock 305) In order to consider the different orientations of the active site residues, docking was performed using four different structures of a Top1-DNA complex The results obtained allowed us to analyze some conformations adopted by the inhibitors during active site binding, confirming the role of hydrogen bond and contributed to clarify the loss of activity due to single point mutations

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TL;DR: Three-dimensional structure of the complex between 4-AQH+ and the binding sites of the K+ pore and the charge distributions and the structures of the binding complexes suggest that the interaction is driven by formation of several hydrogen bonds.
Abstract: We present a molecular docking study aimed to identify the binding site of protonated aminopyridines for the blocking of voltage dependent K+ channels. Several active aminopyridines are considered: 2-aminopyridine, 3-aminopyridine, 4-aminopyridine, 3,4-diaminopyridine, and 4-aminoquinoleine. We apply the AutoDock force field with a lamarckian genetic algorithm, using atomic charges for the ligands derived from the electrostatic potential obtained at the B3LYP/cc-pVDZ level. We find a zone in the α-subunit of the K+ channel bearing common binding sites. This zone corresponds to five amino acids comprised between residuals Thr107 and Ala111, in the KcsA K+ channel (1J95 pdb structure). The 2-aminopyridine, 3-aminopyridine, 4-aminopyridine, and 3,4-diaminopyridine bind to the carboxylic oxygens of Thr107 and Ala111. In all cases aminopyridines are perpendicular to the axis of the pore. 4-aminoquinoleine binds to the carboxylic oxygen of Ala111. Due to its large size, the molecular plane is parallel to the axis of the pore. The charge distributions and the structures of the binding complexes suggest that the interaction is driven by formation of several hydrogen bonds. We find 2-aminopyridine, 3-aminopyridine, 4-aminopyridine, and 3,4-diaminopyridine with similar binding energy. Considering the standard error of the estimate of the AutoDock force field, this energy should lie, as a rough estimation, in the interval 3–7 kcal mol−1. On the other hand, 4-aminoquinoleine seems to have a smaller binding energy.

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TL;DR: Some key features in the series that are responsible for CCR5 antagonistic activity may be used to design more potent 1-(3,3-diphenylpropyl)-piperidinyl derivatives and predict their activity prior to synthesis.
Abstract: 3D-QSAR studies on the derivatives of 1-(3,3-diphenylpropyl)-piperidinyl amide and urea as CCR5 receptor antagonists were performed by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA) methods to rationalize the structural requirements responsible for the inhibitory activity of these compounds. The global minimum energy conformer of the template molecule, the most active and pharmacokinetically stable molecule of the series, was obtained by systematic search and used to build structures of the molecules in the dataset. The best predictions for the CCR5-receptor were obtained with the CoMFA standard model (q (2) = 0.787, r (2) = 0.962) and CoMSIA model combined steric, electrostatic and hydrophobic fields (q (2) = 0.809, r (2) = 0.951). The predictive ability of CoMFA and CoMSIA were determined using a test set of 12 compounds giving predictive correlation coefficients of 0.855 and 0.83, respectively, indicating good predictive power. Further, the robustness of the model was verified by bootstrapping analysis. The contour maps produced by the CoMFA and CoMSIA models were used to identify the structural features relevant to the biological activity in this series. Based on the CoMFA and CoMSIA analysis, we have identified some key features in the series that are responsible for CCR5 antagonistic activity which may be used to design more potent 1-(3,3-diphenylpropyl)-piperidinyl derivatives and predict their activity prior to synthesis.