Automatic search for maximum similarity between molecular electrostatic potential distributions

Summary A new computer program has been developed to automatically obtain the relative position of two molecules in which the similarity between molecular electrostatic-potential distributions is greatest. These distributions are considered in a volume around the molecules, and the similarity is measured by the Spearman rank coefficient. The program has been tested using several pairs of molecules: water vs. water; phenylethylamine and phenylpropylamine vs. benzylamine; and methotrexate vs. dihydrofolic acid.     

Comparative study of the molecular electrostatic potential obtained from different wavefunctions. Reliability of the semiempirical MNDO wavefunction

A systematic analysis of the molecular electrostatic potential (MEP) is presented. This study has been performed with a twofold purpose: first, to study the MEP dependence with regard to the quality of the basis set used to compute the ab initio SCF wavefunction and second, to develop and to assess a new strategy for computing isoelectrostatic potential maps using the semiempirical MNDO wavefunction. The only differences between this procedure and the ab initio SCF MEP computation lie in the freezing of the inner electrons and in the origin of the first-order density matrix. The statistical analysis of MEPs computed for a large number of molecules from MNDO wavefunction and ab initio SCF wavefunctions obtained using STO-3G, 4-31G, 6-31G, 4-31G*, 6-31G*, and 6-31G** basis sets points out the ability of any wavefunction to reproduce the general topological characteristics of the MEP surfaces. Nevertheless, split-valence basis sets including polarization functions are necessary to obtain accurate MEP minimum energy values. MNDO wavefunction tends to overestimate the MEP minima depth by a constant factor and shows an excellent ability to reflect the relative variation of MEP minima energies derived from a rather sophisticated (6-31G*) basis set, lacking of the shortcomings detected in the semiempirical CNDO approximation.     

Similarity of molecular shape

Summary The similarity of one molecule to another has usually been defined in terms of electron densities or electrostatic potentials or fields. Here it is expressed as a function of the molecular shape. Formulations of similarity (S) reduce to very simple forms, thus rendering the computerised calculation straightforward and fast. Elements of similarity are identified, in the same spirit as elements of chirality, except that the former are understood to be variable rather than present-or-absent. Methods are presented which bypass the time-consuming mathematical optimisation of the relative orientation of the molecules. Numerical results are presented and examined, with emphasis on the similarity of isomers. At the extreme, enantiomeric pairs are considered, where it is the dissimilarity (D=1–S) that is of consequence. We argue that chiral molecules can be graded by dissimilarity, and show that D is the shape-analog of the chirality coefficient, with the simple form of the former opening up numerical access to the latter.The late Amatz Meyer was formerly of the Department of Organic Chemistry, Hebrew University, Jerusalem 91904, Israel.     

Quantum chemical study of the molecular patterns of MAO inhibitors and substrates

Similarities and differences between mitochondrial monoamine oxidase (MAO) substrates and inhibitors (both A and B types) are considered, studying quantitatively two molecular properties: electron density and molecular electrostatic potential (MEP ). The following molecules are considered: substrates: PHEA, BZA, tele-N-methyl-histamine, phenylethanolamine, phenylpropylamine, tryptamine, dopamine, phenoxylethylamine, noradrenaline, serotonin, and p-nitro-phenylethanolamine; inhibitors: Deprenil, Clorgyline, and Lilly 51641 (only the moiety involved in the A–B differentiation is considered). The wave functions needed to calculate the analyzed properties are of ab initio quality, and have been calculated in analogous conformations, all near the energetic minima. Electron densities distributions are qualitatively compared by means of a correlation coefficient defined over the whole space. Otherwise, patterns of the possible zones of electrostatic interactions are described by means of the distances and angles between minima, in order to differentiate MAO-A and MAO-B substrates. The results reproduce efficiently the experimental classification and enable us to predict the type of enzymatic action of molecules not yet experimentally classified.     

Comparison of NDDO and quasi-ab initio approaches to compute semiempirical molecular electrostatic potentials

The suitability of the two most widely used strategies to compute semiempirical MEPs is examined. For this purpose, MEP minima, electrostatic charges, and dipoles for a large number of molecules were computed at the AM1, MNDO, and PM3 levels using both the NDDO strategy developed by Ferenczy, Reynolds, and Richards and our own quasi-ab initio method. Results demonstrate that the quasi-ab initio is preferred over the NDDO method for the computation of MEP minima. It is also found that the best set of semiempirical charges and dipoles are obtained using either the AM1 NDDO or the MNDO quasi-ab initio methods. In these two cases, the quality of the results is fully comparable with 6-31G* values. © 1994 by John Wiley & Sons, Inc.     

Use of Molecular Electrostatic Potentials for Analysis of Anticonvulsant Activities of Phenylsuccinimides

Abstract

The present study was performed on a group of 27 derivatives of phenylsuccinimides, of which only 12 were active against maximal electrical shock in spite of the structural similarities of these compounds. The work consisted of four main parts: 1. crystallographic investigations of a subset of chosen compounds; 2. conformational analysis of characteristic molecules from the investigated series, performed by means of molecular mechanics calculations; 3. molecular orbital optimization of all the molecules using the MNDO method starting with conformations obtained in 2; 4. molecular electrostatic potential (MEP) analysis which was performed on the semiempirical (MNDO) and ab initio levels. This research showed that MEP maps provide a signature that distinguishes between active and inactive compounds. There are MEP minima close to the two carbonyl oxygens of the imide ring, and although the magnitude of the difference between the two minima is approximately constant, the sign of the difference provides an activity index. The initial orientations of phenylsuccinimide molecules in relation to the receptor are not equivalent and they depend on the potential distribution around both the succinimide molecules and around the receptor. In the active compounds the negative potential difference at the discussed points most probably influences the initial set-up of the molecules in relation to the receptor and results in a considerably higher probability of the molecules being bound at the right place on the receptor.     

Theoretical studies of the mechanism of the action of the neurohypophyseal hormones. I. Molecular electrostatic potential (MEP) and molecular electrostatic field (MEF) maps of some vasopressin analogues

Summary Continuing our theoretical studies of the oxytocin and vasopressin analogues, we have analysed the molecular electrostatic potential (MEP) and the norm of the molecular electrostatic field (MEF) of [1--mercaptopropionic acid]-arginine-vasopressin ([Mpa¹]-AVP), [1-(-mercapto-,-cyclopentamethylene)propionic acid]-arginine-vasopressin ([Cpp]-AVP), and [1-thiosalicylic acid]-arginine-vasopressin ([Ths]-AVP) whose low-energy conformations were calculated in our previous work. These compounds are known from experiment to exhibit different biological activity. The scalar fields mentioned determine the energy of interaction with either charged (MEP) or polar (MEF) species, the energy being in the second case either optimal or Boltzmann-averaged over all the possible orientations of the dipole moment versus the electrostatic field. The electrostatic interactions slowly vanish with distance and can therefore be considered to be the factor determining the molecular shape at greater distances, which can help in both predicting the interactions with the receptor at the stage of remote recognition and in finding the preferred directions of solvation by a polar solvent. In the analysis of the fields three techniques have been used: (i) the construction of maps in certain planes; (ii) the construction of maps on spheres centered in the charge center of the molecule under study and of poles chosen according to the main axes of the quadrupole moment; and (iii) the construction of surfaces corresponding to a given value of potential. The results obtained show that the shapes of both MEP and MEF are similar in the case of [Mpa¹]-AVP and [Cpp¹-AVP (biologically active), while some differences emerge when comparing these compounds with [Ths¹]-AVP (inactive). It has also been found that both MEP and MEF depend even more strongly on conformation.     

π-SCF-Molecular Mechanics PIMM: Formulation,parameters, applications

Summary A -SCF/Molecular Mechanics method (PIMM) for the calculation of heats of formation, molecular geometries and charge density distributions of organic molecules is described. The method combines a -SCF molecular orbital calculation and the -charge evaluation procedure PEOE of Marsilli and Gasteiger with molecular mechanics. The formulas and parameters use are given. A series of results for small molecules is presented and compared with experimental data.     

Novel algorithms for searching conformational space

Summary The modelling of biological molecules by molecular dynamics is beset by a range of problems. The most important of these is the multiple-minima problem. The deep metastable minima can cause difficulties in proper equilibration of a molecular system and result in the simulated system being trapped in a long-lived metastable state. One way to overcome these problems is to re-engineer the Newtonian Rules in order to more efficiently search conformational space. Re-engineering of the Newtonian Rules implies a redesign of the physical laws arising from them. This is done in various ways by the RUSH, Hybrid Monte Carlo and PEACS algorithms. This paper explores applications of these algorithms, and compares them to a traditional molecular dynamics method.     

Quantitative comparison of molecular electrostatic potential distributions from several semiempirical and ab initio wave functions

A quantitative comparative analysis of molecular electrostatic potential (MEP) distributions generated from different wave functions was carried out. Wave functions were computed by using MNDO, AMl, STO-3G, 3-21G, 4-31G, 6-31G, 4-31G*, 6-31G*, and 6-31G** methods. Ten different compounds, which include usual atoms and groups of biomolecules, such as hydroxyl, carbonyl, amine, amide, imine, double and triple bonds, and heteroaromatic rings, were studied. For each compound, MEP values in the points of a common 3-D grid were computed; thereafter, the similarity between each pair of MEP distributions generated by different methods was assessed. Similarities were measured using the Spearman rank correlation coefficient. A similarity matrix was obtained for each compound. Similarity matrices were averaged and a hierarchical cluster analysis was carried out to classify the different quantum chemical methods. In the compounds studied, the main conclusion is the negligible difference between the pattern of MEP distributions generated from all split valence basis sets (with and without polarization functions). © 1993 John Wiley & Sons, Inc.     

Insight into the acidic behavior of oxazolidin-2-one,its thione and selone analogs through computational techniques

Deprotonation thermochemistry of Oxazolidin-2-one (OXA), Oxazolidine-2-thione (OXA-S), and Oxazolidine-2-selone (OXA-Se) has been studied in order to find the most acidic site and relative acidities of these heterocyclics at various sites. The deprotonation enthalpies at MP2/6-311++G**//MP2/6-31+G* and B3LYP/6-31+G* levels, while the free energies for deprotonation process and pKa values at B3LYP/6-31+G* level both in gas and aqueous phase (using PCM continuum model) of the anions of the three heterocyclics have been computed at 298 K. Calculated aqueous phase pKa values of OXA vary by ~6–7 units from the experimental aqueous phase pKa values of OXA and its derivatives. The deprotonation at the nitrogen is favored in OXA over the carbon atoms in contrast to the OXA-S and OXA-Se where in the deprotonation at the carbon attached to the nitrogen is most preferred. Deprotonation at this carbon induces an important C–O bond rupture in OXA-S and OXA-Se promoting an energetically favored ring-opening process. The finding offers a rare case when C–H acidity is able to dominate over the N–H acidity. In order to explain the relative stabilities, relative acidities and deprotonation enthalpies various characteristics of these molecules as well as their anions such as molecular electrostatic potential surface (MEP), frontier molecular orbital (FMO) features, chemical hardness, softness have been governed. The three dimensional MEP maps and HOMO–LUMO orbitals encompassing these molecules yield a reliable relative stability and reactivity (in terms of acidity) map displaying the most probable regions for deprotonation. The differential distribution of the electrostatic potential over the neutral and anionic species of OXA, OXA-S, and OXA-Se molecules is authentically reflected by HOMO–LUMO orbitals and NBO charge distribution analysis. The lone pair occupancies, second order delocalization energies for orbital interactions and the distribution of atomic charges over the entire molecular framework as obtained from natural bond orbital (NBO) analysis are found to faithfully replicate the predictions from the MEP maps and HOMO–LUMO band gaps in respect of explaining the relative stabilities and acidities in most of the cases. Good linear correlations have been obtained between HOMO–LUMO gap and pKa values in the aqueous phase for OXA and OXA-S molecules.     

Similarity searching in files of three-dimensional chemical structures: Representation and searching of molecular electrostatic potentials using field-graphs

This paper reports a method for the identification of those molecules in a database of rigid 3D structures with molecular electrostatic potential (MEP) grids that are most similar to that of a user-defined target molecule. The most important features of an MEP grid are encoded in field-graphs, and a target molecule is matched against a database molecule by a comparison of the corresponding field-graphs. The matching is effected using a maximal common subgraph isomorphism algorithm, which provides an alignment of the target molecule's field- graph with those of each of the database molecules in turn. These alignments are used in the second stage of the search algorithm to calculate the intermolecular MEP similarities. Several different ways of generating field-graphs are evaluated, in terms of the effectiveness of the resulting similarity measures and of the associated computational costs. The most appropriate procedure has been implemented in an operational system that searches a corporate database, containing ca. 173,000 3D structures.     

Modeling and conformation analysis of β-cyclodextrin complexes

Summary A series of -cyclodextrin complexes containing various guest molecules was studied using computer-aided molecular modeling and conformation analysis techniques. The geometry of each complex was studied using crystallographic data. The positions of the glycosidic O4 atoms indicate that the -cyclodextrin molecules are elliptically distorted. This distortion can be related to the van der Waals volume of the guest molecules. This correlation is different for aromatic and non-aromatic guest compounds. Rigid body docking experiments demonstrated that in crystal structures the guest molecule occupies a position in the cavity of nearly minimum interaction energy when there are no other molecules having interactions with the guest molecule. From the crystallographic data several rules could be deduced which seem to determine the conformation of -cyclodextrin molecules in complexes. A procedure was developed to construct -cyclodextrin molecules that are able to encompass guest molecules having a given van der Waals volume.     

An optimized AM1/MST method for the MST-SCRF representation of solvated systems

The AM1/MST strategy for the computation of hydrated neutral molecules has been optimized. For this purpose, we have systematically explored the best cavity definition, the most suitable strategy to compute the molecular electrostatic potential (MEP), and the use of MEP scaling factors to correct the semiempirical MEPs. As a result, we have developed an optimized version of the AM1/MST method, which allows us to reproduce well the experimental free energies of hydration (root mean square, rms, deviation in the range of 1 kcal/mol) as well as the water-induced dipoles computed at the 6-31G*/MST level (rms deviations in the range of 0.3 D). © 1994 by John Wiley & Sons, Inc.     

Crystal Structures of Twisted Di(2-Pyridyl)ketone and Planar Azo-di(2-Pyridine) and Their Discussion Based on PM3 Enthalpy Hypersurfaces for the Isoelectronic Molecules

Single crystal structure determinations prove the two pyridine substituents in di(2-pyridyl)ketone (H₄C₄NC)₂C=O to be twisted out of the carbonyl skeleton plane by torsion angles (OCCN) of 41° and –163°, in contrast to their planar arrangement in azo-di(2-pyridine) H₄C₄NC)-N=N-(CNC₄H₄). In order to rationalize the surprising difference between the two isoelectronic molecules, approximate PM3 enthalpy of formation hypersurfaces have been calculated for each of the two ring torsions, which are assumed to be the dominant ones among the 3N – 6 = 60 degrees of freedom. For both the ketone and the azo derivative, global minima are calculated, the torsion angles of which deviate from the crystal structure results, and, therefore, support the assumption that both the experimentally determined twisting of di(2-pyridyl)ketone as well as the flattening of azo-di(2-pyridine) might be affected by the crystal packing.     

Near ab initio quality molecular electrostatic potential maps using hybridization displacement charges at PM3 level and effects of geometrical changes in amino groups

Charge distributions, dipole moments, and molecular electrostatic potentials (MEP) around several molecules consisting of carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine atoms were studied using the PM3 semiempirical method and the results compared with those obtained using ab initio calculations at the RHF/6‐31G** level. Thus it is shown that relative MEP values near different atoms can be obtained using hybridization displacement charges (HDC) obtained by employing PM3 density matrices that usually agree quite satisfactorily with the ab initio ones. Further, positions of ab initio MEP minima are correctly located and the corresponding relative MEP values usually correctly predicted using the PM3(HDC) charges distributed continuously in three dimensions according to the forms of squares of valence s atomic orbitals. The necessary parameters for HDC calculations using the PM3 method were optimized. It is shown how within the frameworks of both PM3 and AM1 methods the π electrons or lone pairs associated with amino group nitrogen atoms and ring atoms can be satisfactorily treated in different situations. © 2001 John Wiley & Sons, Inc. Int J Quant Chem 82: 299–312, 2001     

The matching of electrostatic extrema: A useful method in drug design? A study of phosphodiesterase III inhibitors

Summary Ligands which bind to a specific protein binding site are often expected to have a similar electrostatic environment which complements that of the binding site. One method of assessing molecular electrostatic similarity is to examine the possible overlay of the maxima and minima in the electrostatic potential outside the molecules and thereby match the regions where strong electrostatic interactions, including hydrogen bonds, with the residues of the binding site may be possible. This approach is validated with accurate calculations of the electrostatic potential, derived from a distributed multipole analysis of an ab initio charge density of the molecule, so that the effects of lone pair and -electron density are correctly included. We have applied this method to the phosphodiesterase (PDE) III substrate adenosine-3,5-cyclic monophosphate (cAMP) and a range of nonspecific and specific PDE III inhibitors. Despite the structural variation between cAMP and the inhibitors, it is possible to match three or four extrema to produce relative orientations in which the inhibitors are sufficiently sterically and electrostatically similar to the natural substrate to account for their affinity for PDE III. This matching of extrema is more apparent using the accurate electrostatic models than it was when this approach was first applied, using semiempirical point charge models. These results reinforce the hypothesis of electrostatic similarity and give weight to the technique of extrema matching as a useful tool in drug design.     

空间距离在三维分子相似度计算中的应用

采用Tripos公司的MOPAC模块计算分子的空间距离,所得距离矩阵用带有约束条件的空间距离方法计算分子的相似度,同时通过4组化合物的计算,与纯空间距离方法进行比较,得到了较为满意的结果。     

Conformational analysis of a stereochemically complete set of cis-enediol peptide analogues

A conformational analysis of a stereochemically complete set of peptide analogues based on a cis-enediol unit is presented. The cis-enediol unit, which can replace a two or a three amino acid segment of a peptide, contains two "side chains", four asymmetrical carbon atoms, and six free dihedral angles. To determine the accessible conformational space, the molecules are divided into three fragments, each containing two free dihedral angles. The energy surfaces are computed for all dihedral angle values, and the possible conformations of the cis-enediol unit analogues are built using all combinations of the surface minima. Such a "build-up" procedure, which is very fast, is able to reproduce 75% of the minima obtained from a full dihedral angle exploration of the conformational space. The cis-enediol unit minima are compared with the corresponding di- and tripeptide minima; all peptide minima can be closely matched by a cis-enediol unit minimum of low energy (less than 2.2 kcal/mol above the lowest energy conformer). However, there are low energy minima of the cis-enediol unit that have no corresponding minima in peptides. The results are shown to depend strongly on the chirality of the analogues. The ability of each of the stereoisomers to mimic natural peptides, evaluated by the present approach, is correlated with its experimental activity in a renin inhibition assay.