Structure-activity relationships for apomorphine congeners. Conformational energies vs. biological activities

Summary A series of apomorphine congeners has been studied with respect to their ability to mimic the structural requirements of the dopamine pharmacophore in the potent and stereoselective dopamine receptor agonist (R)-apomorphine. Conformational energies of the mimicking structures calculated by molecular mechanics (MMP2) correlate well with the observed biological activities.     

Conformational calculations on odoriferous molecules of sandalwood,I. The search for the odoriferous principle of sandalwood oil

The conformations of two relatively rigid molecules with sandalwood odor have been investigated by molecular mechanics and the semiempirical method AM1. A comparison between both geometries shows that a common structural element exists in the relative rearrangement of a carbinol function and a quarternary carbon atom. The distance of these two centers as well as the electron density agree well in both structures.

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Rechnungen zur Konformation von Molekülen mit Sandelholzgeruch, 1. Mitt.: Die Suche nach dem Geruchsprinzip des Sandelholzöles

Zusammenfassung Die Konformationen zweier relativ starrer Moleküle mit Sandelholzgeruch wurden mit molekularmechanischer und mit einer semiempirischen Methode (AM1) bestimmt. Ein Vergleich der beiden molekularer Geometrien zeigt ein gemeinsames Strukturelement und zwar die relative Anordnung der Carbinolfunktion zu einem quartären Kohlenstoffatom. Sowohl deren Abstand als auch deren Elektronendichte stimmen in beiden Verbindungen überein.

     

Molecular modeling of intercalation complexes of antitumor active 9-aminoacridine and a [d,e]-anellated isoquinoline derivative with base paired deoxytetranucleotides

Summary Intercalators are molecules capable of sliding between DNA base pairs without breaking up the hydrogen bonds between the DNA bases. On the basis of molecular mechanics calculations structural, models of B-DNA tetranucleotide intercalation complexes of some cytostatic active 9-aminoacridines and of a [d, e]-anellated isoquinoline derivative are presented. The drug complexes are stabilized by energetically favouredvan der Waals interactions and by selective hydrogen bonds between the side chains of the drugs and the DNA bases. Semiempirical quantum chemistry calculations revealed that the chromophoric system of the intercalators is able to form ,-charge-transfer interactions with the purine bases of the base paired deoxytetranucleotides. The theoretical findings are of interest for a more specific drug design of cytostatically active agents.

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Molecular Modeling von Interkalationskomplexen antitumoraktiver 9-Aminoacridine sowie eines [d, e]-anellierten Isochinolinderivates mit basengepaarten Desoxytetranukleotiden

Zusammenfassung Interkalatoren sind Moleküle, die in der Lage sind, sich zwischen DNA-Basenpaare einzulagern, ohne die Wasserstoffbrücken zwischen den DNA-Basen aufzubrechen. Auf der Basis von molekülmechanischen Rechnungen werden Tetranukleotid-Interkalationskomplexe von verschiedenen zytostatisch aktiven 9-Aminoacridinen und von einem [d, e]-anellierten Isochinolinderivat präsentiert. Die Komplexe werden durch energetisch günstigevan der Waals-Interaktionen sowie durch selektive Wasserstoffbrückenbindungen zwischen den Seitenketten der Wirkstoffe und den DNA-Basen stabilisiert. Semiempirische quantenchemische Rechnungen ergaben, daß der Chromophor der Interkalatoren in der Lage ist, ,-charge-transfer Wechselwirkungen mit den Purinbasen der basengepaarten Desoxytetranukleotide auszubilden. Die theoretischen Ergebnisse sind für ein spezifischeres Wirkstoffdesign zytostatisch aktiver Verbindungen von Interesse.

     

A Monte Carlo pharmacophore generation procedure: Application to the human PAF receptor

Summary A novel pharmacophore definition procedure is described, which uses a Monte Carlo method to superimpose molecules. Pharmacophore space is searched by a technique similar to high temperature annealing. Subsequent refinement of candidate pharmacophores by energy minimization produces low-energy conformations that may be involved in receptor binding. The method has been applied to compounds that bind to the human platelet-activating factor (PAF) receptor. Alternative binding site models for the PAF receptor are presented and discussed.A preliminary account of this work has been published elsewhere [1].     

Evidence that there is a future for semiempirical molecular orbital calculations

The frequency of use and discussion of semiempirical and ab initio software is traced with bibliometric data from the Current Journals of the American Chemistry Society (JCACS) database, which has complete papers published in 19 journals in various fields of chemistry. Not only is the use of all types of computational chemistry software increasing apace, but also the number of papers mentioning semiempirical programs as a percentage of all papers mentioning quantum chemistry programs is growing. This percentage referring to semiempirical molecular orbital software grew from 29% in 1989 to 34% in 1993.     

Computer simulation of the binding of quinocarcin to DNA. Prediction of mode of action and absolute configuration

Summary Computer-based models were derived for the covalent and noncovalent binding of the antitumor antibiotic quinocarcin to a representative DNA segment, d(ATGCAT)₂. They showed that a mode of action, involving opening of the oxazolidine ring to give an iminium ion, followed by initial noncovalent binding in the minor groove and subsequent alkylation of the 2-amino group of guanine, was rational and attended by favorable interaction energies in each step. The best model had the aryl ring of quinocarcin lying in the 3 direction from the covalent binding site and anR configuration at the carbon involved in covalent bond formation. It also showed that the preferred absolute configuration for quinocarcin was the reverse of that arbitrarily assigned in the literature.     

On the rhodanines and their presence in biologically active ligands

An innovative use of cluster analysis is presented to compare the output from different levels of theory. A dendrogram shows the relative energies of the tautomers of methylidene rhodanine (5-methylene-2-thioxo-thiazolidin-4-one), computed by the semiempirical molecular orbital method AM1, are remarkably similar to the ab initio values from the LANL2DZ++(d,p) basis set, which involves effective core potentials augmented by polarization and diffuse functions. However, the optimized bond lengths and bond angles at the AM1 and AM1/SM1 levels do not agree well with those obtained at the 6–31G^* and LANL2DZ++(d,p) levels of theory or with experiment. Database searching is used to obtain an indication of how common the rhodanine ring is. The prevalence of rhodanine-containing compounds of pharmaceutical interest is very small despite the fact that the compounds exhibit a wide variety of bioactivity.     

A Conformational Study on Silacyclohexane. Comparison of ab initio (HF,MP2), DFT,and Molecular Mechanics Calculations. Conformational Energy Surface of Silacyclohexane

The structures and relative energies for the basic conformations of silacyclohexane 1 have been calculated using HF, RI‐MP2, RI‐DFT and MM3 methods. All methods predict the chair form to be the dominant conformation and all of them predict structures which are in good agreement with experimental data. The conformational energy surface of 1 has been calculated using MM3. It is found that there are two symmetric lowest energy pathways for the chair‐to‐chair inversion. Each of them consists of two sofa‐like transition states, two twist forms with C₁ symmetry (twist‐C₁), two boat forms with Si in a gunnel position (C₁ symmetry), and one twist form with C₂ symmetry (twist‐C₂). All methods calculate the relative energy to increase in the order chair < twist‐C₂ < twist‐C₁ < boat. At the MP2 level of theory and using TZVP and TZVPP (Si atoms) basis sets the relative energies are calculated to be 3.76, 4.80, and 5.47 kcal mol^–1 for the twist‐C₂, twist‐C₁, and boat conformations, respectively. The energy barrier from the chair to the twisted conformations of 1 is found to be 6.6 and 5.7 kcal mol^–1 from MM3 and RI‐DFT calculations, respectively. The boat form with Si at the prow (C_s symmetry) does not correspond to a local minimum nor a saddle point on the MM3 energy surface, whereas a RI‐DFT optimization under C_s symmetry constraint resulted in a local minimum. In both cases its energy is above that of the chair‐to‐twist‐C₁ transition state, however, and it is clearly not a part of the chair‐to‐chair inversion.     

Cavity search: An algorithm for the isolation and display of cavity-like binding regions

Summary A set of algorithms designed to enhance the display of protein binding cavities is presented. These algorithms, collectively entitled CAVITY SEARCH, allow the user to isolate and fully define the extent of a particular cavity. Solid modeling techniques are employed to produce a detailed cast of the active site region, which can then be color-coded to show electrostatic and steric interactions between the protein cavity and a bound ligand.     

Structural study of pyrimidine nucleoside analogues. I: Molecular mechanics and semiempirical calculations of 2′-deoxy-2′-fluoroarabinofuranosyluracils

Molecular mechanics (MM) calculations have been performed on the title compounds. For the MM minimum energy conformation obtained by conformational analysis, molecular orbital (MO) calculations (MNDO and AM1) have also been performed. The geometries obtained have been compared with the experimental ones extracted from the Cambridge Structural Database (CSD). A qualitative structure-activity relationship has been pointed out based on the electrostatic potentials calculated at different positions on the electronic surface.     

Molecular similarity studies on sandalwood odour molecules: Investigations of the conformational space

Summary Odour differences of some campholene and fencholene derivatives are explained by the analysis of the conformational space and the molecular shape of these molecules. The high flexibility caused by free rotation of some carbon-carbon bonds leads in one case to a large number of energetically possible conformations which have to be taken into account for a study of molecular similarity. In another case, steric restrictions reduce the number of relevant conformations such that no active conformation exists in a thermodynamic equilibrium.Conformational Calculations on Sandalwood Odour XII; for part XI, see Ref. [1]     

Local elevation: A method for improving the searching properties of molecular dynamics simulation

Summary The concept of memory has been introduced into a molecular dynamics algorithm. This was done so as to persuade a molecular system to visit new areas of conformational space rather than be confined to a small number of low-energy regions. The method is demonstrated on a simple model system and the 11-residue cyclic peptide cyclosporin A. For comparison, calculations were also performed using simulated temperature annealing and a potential energy annealing scheme. Although the method can only be applied to systems with a small number of degrees of freedom, it offers the chance to generate a multitude of different low-energy structures, where other methods only give a single one or few. This is clearly important in problems such as drug design, where one is interested in the conformational spread of a system.     

Theoretical analysis of binding specificity of influenza viral hemagglutinin to avian and human receptors based on the fragment molecular orbital method

The hemagglutinin (HA) protein of the influenza virus binds to the host cell receptor in the early stage of viral infection. A change in binding specificity from avian 2-3 to human 2-6 receptor is essential for optimal human-to-human transmission and pandemics. Therefore, it is important to reveal the key factors governing the binding affinity of HA-receptor complex at the molecular level for the understanding and prediction of influenza pandemics. In this work, on the basis of ab initio fragment molecular orbital (FMO) method, we have carried out the interaction energy analysis of HA-receptor complexes to quantitatively elucidate the binding specificity of HAs to avian and human receptors. To discuss the binding property of influenza HA comprehensively, a number of HAs from human H1, swine H1, avian H3 and avian H5 viruses were analyzed. We performed detailed investigations about the interaction patterns of complexes of various HAs and receptor analogues, and revealed that intra-molecular interactions between conserved residues in HA play an important role for HA-receptor binding. These results may provide a hint to understand the role of conserved acidic residues at the receptor binding site which are destabilized by the electrostatic repulsion with sialic acid. The calculated binding energies and interaction patterns between receptor and HAs are consistent with the binding specificities of each HA and thus explain the receptor binding mechanism. The calculated results in the present analysis have provided a number of viewpoints regarding the models for the HA-receptor binding specificity associated with mutated residues. Examples include the role of Glu190 and Gln226 for the binding specificity of H5 HA. Since H5 HA has not yet been adapted to human receptor and the mechanism of the specificity change is unknown, this result is helpful for the prediction of the change in receptor specificity associated with forthcoming possible pandemics.     

Molecular Mechanics Modeling of the Interactions between the Active Domain of CAP18106–137 and Lipid A

In this work, a computer search with molecular mechanics calculations is applied to determine the possible low-energy configurations of two adjacent molecules, CAP18_106–137 and lipid A. This computer search is performed by systematically searching the five degrees of freedom that define the relative orientations of the two adjacent molecules. Hydrophilic and hydrophobic units are separated into several small domains along the CAP18_106–137 molecule so that it can interact with the lipid A either through the Coulombic interactions with the diphosphoryl head group or through the hydrophobic interactions with the fatty acyl chains. The intermolecular interactions are calculated through the van der Waals and Coulombic interactions. The Coulombic interactions are calculated by using a dielectric constant either with a value of unity ϵ = 1 or with a distance-dependent dielectric function ϵ(r) = r_ij. Based on the 400 lowest searched configurations, the intermolecular interactions calculated with ϵ = 1 are found to be about sevenfold lower than those calculated with ϵ(r) = r_ij. Based on the inspection of the sixteen snapshots of molecular associations, the hydrophobic interactions calculated with ϵ(r) = r_ij are more favorable than those calculated with ϵ = 1. The high population of the lipid A binding to the CAP 18_106–137 molecule is located within the first 19 residues near the N-terminus of the peptide, as calculated either with e = 1 or with ϵ(r) = r_ij, by observing the diphosphoryl groups of the lipid A. The orientations of the lipid A with respect to the CAP18_106–137 molecule complete an angle of 260°, which appose to the positively charged residues in the N-terminal half by using the helical wheel projection of the peptide.     

On the suitability of semiempirical calculations as sources of force field parameters

Summary The suitability of Dewar's Hamiltonians as a source of bonded force field parameters is explored from the comparison analysis between up to 270 semiempirically derived force field parameters and experimentally derived values reported in some of the most popular force fields. From the statistical analysis of the results, some general conclusions about the semiempirical parametrization are formulated.     

Synthesis and theoretical study of first generation CCK-functional dendrimers

A convenient synthesis and theoretical study of five CCK-functional dendrimers is described.The dendritic cores were linked with the CCK(Trp-Met-Asp(OBn)-PheNH2) fragment by forming amide bonds to give five target molecules.The structures of CCK-functional dendrimers were characterized by NMR,MS spectrum and predicted using molecular mechanics and PM3 semi- empirical molecular orbital theory.     

Synthesis and dopamine receptor binding affinity of 4H-thiochromenoapomorphines

Abstract  The synthesis of 4H-thiochromene derivatives of apomorphines, a novel class of isoquinoline alkaloid-related compounds, has been achieved by different O-dealkylation methods applied on previously published heteroring-fused aporphinoids. Detailed DFT study has been presented regarding the mechanism of the L-selectride-mediated multiple O-dealkylation of a seven-ring aporphine analogue. Dopamine-binding tests confirmed the essential function of 11-hydroxy moiety of the aporphine skeleton and revealed a remarkable D₁ over D₂ specificity for the derivative having the 4H-thiochromene ring system attached to positions 2 and 3 of the aporphine backbone. Graphical Abstract  

Molecular Modeling Studies on Molecular Recognition: Crown Ethers,Cryptands and Cryptates. From Static Models in vacuo to Dynamical Models in Solution

Abstract

Molecular Mechanics, Monte Carlo and Molecular Dynamics simulations on free and complexed crown ethers, on bicyclic cryptands and cryptates provide deeper insights into their conformational and recognition properties and allow to address the questions of preorganisation, complementarity, and binding selectivity. Alternatively, references to experimental data allow to outline present theoretical and computational limitations. Of particular interest are the microscopic pictures obtained in solution, which demonstrate the importance of solvent and environment effects on the precise structure of free and complexed receptors, and on their dynamics. Quantitative insights into relative free energies in solution represents a most promising breakthrough for computational studies in molecular recognition.     

Protein‐specific force field derived from the fragment molecular orbital method can improve protein–ligand binding interactions

Accurate computational estimate of the protein–ligand binding affinity is of central importance in rational drug design. To improve accuracy of the molecular mechanics (MM) force field (FF) for protein–ligand simulations, we use a protein‐specific FF derived by the fragment molecular orbital (FMO) method and by the restrained electrostatic potential (RESP) method. Applying this FMO‐RESP method to two proteins, dodecin, and lysozyme, we found that protein‐specific partial charges tend to differ more significantly from the standard AMBER charges for isolated charged atoms. We did not see the dependence of partial charges on the secondary structure. Computing the binding affinities of dodecin with five ligands by MM PBSA protocol with the FMO‐RESP charge set as well as with the standard AMBER charges, we found that the former gives better correlation with experimental affinities than the latter. While, for lysozyme with five ligands, both charge sets gave similar and relatively accurate estimates of binding affinities. © 2013 Wiley Periodicals, Inc.     

Theoretical study of the binding nature of glassy carbon with nickel(II) phthalocyanine complexes

A theoretical study at the semiempirical RHF/PM3(tm) level (tm: transition metal) of the binding nature between a glassy carbon (GC) cluster and a nickel(II) complex (nickel(II) phthalocyanine NiPc, nickel(II) tetrasulphophthalocyanine NiTSPc) was performed. Three types of interactions for GC?NiPc (NiTSPc) were studied: (a) through an oxo (O) bridge, (b) through an hydroxo (OH) bridge, and (c) non-bridge. One layer (NiPc, NiTSPc) and two layers (NiPc?NiPc) of complex were considered. The binding energy calculated showed that in both cases NiPc and NiTSPc, the oxo structures are more stable than the hydroxo ones, and than the non-bridge systems. Charge analysis (NAO) predicted that GC gained more electrons in an oxo structure than in the analogues hydroxo. The theoretical results showed an agreement with the experimental data available, an oxo binding between GC and a nickel complex (NiPc, NiTSPc) in aqueous alkaline solutions is formed.