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Conformational Space (conformational + space)
Selected AbstractsConformational spaces of the gastrointestinal antisecretory chiral drug omeprazole: Stereochemistry and tautomerismCHIRALITY, Issue 1 2006Hava Caner Abstract A study of the conformational spaces of the chiral proton pump inhibitor (PPI) drug omeprazole by semiempirical, ab-initio, and DFT methods is described. In addition to the chiral center at the sulfinyl sulfur atom, the chiral axis at the pyridine ring (due to the hindered rotation of the 4-methoxy substituents) was considered. The results were analyzed in terms of the 5-methoxy and 6-methoxy tautomers and the two pairs of enantiomers (R,P)/(S,M) and (R,M)/(S,P). Five torsion angles were systematically explored: the backbone rotations defined by D1 (N3,C2,S10,O11), D2 (C2,S10,C12,C13), and D3 (S10,C12,C13,N14) and two methoxy rotations defined by D4 (C6,C5,O8,C9) and D5 (C16,C17,O19,C20). Significant energy differences were revealed between the 5- and 6-methoxy tautomers, the extended and folded conformations, and the (S,M) and (S,P) diastereomers. The "extended M" conformation of the 6-methoxy tautomer of (S)-omeprazole was found to be the most stable conformer. © 2005 Wiley-Liss, Inc. Chirality [source] Ramachandran-type plots for glycosidic linkages: Examples from molecular dynamic simulations using the Glycam06 force fieldJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 6 2009Amanda M. Salisburg Abstract The goals of this article are to (1) provide further validation of the Glycam06 force field, specifically for its use in implicit solvent molecular dynamic (MD) simulations, and (2) to present the extension of G.N. Ramachandran's idea of plotting amino acid phi and psi angles to the glycosidic phi, psi, and omega angles formed between carbohydrates. As in traditional Ramachandran plots, these carbohydrate Ramachandran-type (carb-Rama) plots reveal the coupling between the glycosidic angles by displaying the allowed and disallowed conformational space. Considering two-bond glycosidic linkages, there are 18 possible conformational regions that can be defined by (,, ,, ,) and (,, ,, ,), whereas for three-bond linkages, there are 54 possible regions that can be defined by (,, ,, ,, ,) and (,, ,, ,, ,). Illustrating these ideas are molecular dynamic simulations on an implicitly hydrated oligosaccharide (700 ns) and its eight constituent disaccharides (50 ns/disaccharide). For each linkage, we compare and contrast the oligosaccharide and respective disaccharide carb-Rama plots, validate the simulations and the Glycam06 force field through comparison to experimental data, and discuss the general trends observed in the plots. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2009 [source] Toward accurate relative energy predictions of the bioactive conformation of drugsJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 4 2009Keith T. Butler Abstract Quantifying the relative energy of a ligand in its target-bound state (i.e. the bioactive conformation) is essential to understand the process of molecular recognition, to optimize the potency of bioactive molecules and to increase the accuracy of structure-based drug design methods. This is, nevertheless, seriously hampered by two interrelated issues, namely the difficulty in carrying out an exhaustive sampling of the conformational space and the shortcomings of the energy functions, usually based on parametric methods of limited accuracy. Matters are further complicated by the experimental uncertainty on the atomic coordinates, which precludes a univocal definition of the bioactive conformation. In this article we investigate the relative energy of bioactive conformations introducing two major improvements over previous studies: the use sophisticated QM-based methods to take into account both the internal energy of the ligand and the solvation effect, and the application of physically meaningful constraints to refine the bioactive conformation. On a set of 99 drug-like molecules, we find that, contrary to previous observations, two thirds of bioactive conformations lie within 0.5 kcal mol,1 of a local minimum, with penalties above 2.0kcal mol,1 being generally attributable to structural determination inaccuracies. The methodology herein described opens the door to obtain quantitative estimates of the energy of bioactive conformations and can be used both as an aid in refining crystallographic structures and as a tool in drug discovery. © 2008 Wiley Periodicals, Inc. J Comput Chem 2009 [source] DFT conformational studies of ,-maltotriose,JOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 7 2008Udo Schnupf Abstract Recent DFT optimization studies on ,-maltose improved our understanding of the preferred conformations of ,-maltose. The present study extends these studies to ,-maltotriose with three ,- D -glucopyranose residues linked by two ,-[1,4] bridges, denoted herein as DP-3's. Combinations of gg, gt, and tg hydroxymethyl groups are included for both "c" and "r" hydroxyl rotamers. When the hydroxymethyl groups are for example, gg-gg-gg, and the hydroxyl groups are rotated from all clockwise, "c", to all counterclockwise, "r", the minimum energy positions of the bridging dihedral angles (,H and ,H) move from the region of conformational space of (,, ,), relative to (0°, 0°), to a new position defined by (+, +). Further, it was found previously that the relative energies of ,-maltose gg-gg-c and "r" conformations were very close to one another; however, the DP-3's relative energies between hydroxyl "c" or "r" rotamers differ by more than one kcal/mol, in favor of the "c" form, even though the lowest energy DP-3 conformations have glycosidic dihedral angles similar to those found in the ,-maltose study. Preliminary solvation studies using COSMO, a dielectric solvation method, point to important solvent contributions that reverse the energy profiles, showing an energy preference for the "r" forms. Only structures in which the rings are in the chair conformation are presented here. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2008 [source] On searching in, sampling of, and dynamically moving through conformational space of biomolecular systems: A reviewJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 2 2008Markus Christen Abstract Methods to search for low-energy conformations, to generate a Boltzmann-weighted ensemble of configurations, or to generate classical-dynamical trajectories for molecular systems in the condensed liquid phase are briefly reviewed with an eye to application to biomolecular systems. After having chosen the degrees of freedom and method to generate molecular configurations, the efficiency of the search or sampling can be enhanced in various ways: (i) efficient calculation of the energy function and forces, (ii) application of a plethora of search enhancement techniques, (iii) use of a biasing potential energy term, and (iv) guiding the sampling using a reaction or transition pathway. The overview of the available methods should help the reader to choose the combination that is most suitable for the biomolecular system, degrees of freedom, interaction function, and molecular or thermodynamic properties of interest. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2008 [source] Conformational analysis by intersection: CONANJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 1 2003Andrew Smellie Abstract As high throughput techniques in chemical synthesis and screening improve, more demands are placed on computer assisted design and virtual screening. Many of these computational methods require one or more three-dimensional conformations for molecules, creating a demand for a conformational analysis tool that can rapidly and robustly cover the low-energy conformational spaces of small molecules. A new algorithm of intersection is presented here, which quickly generates (on average <0.5 seconds/stereoisomer) a complete description of the low energy conformational space of a small molecule. The molecule is first decomposed into nonoverlapping nodes N (usually rings) and overlapping paths P with conformations (N and P) generated in an offline process. In a second step the node and path data are combined to form distinct conformers of the molecule. Finally, heuristics are applied after intersection to generate a small representative collection of conformations that span the conformational space. In a study of ,97,000 randomly selected molecules from the MDDR, results are presented that explore these conformations and their ability to cover low-energy conformational space. © 2002 Wiley Periodicals, Inc. J Comput Chem 24: 10,20, 2003 [source] Modeling an active conformation for linear peptides and design of a competitive inhibitor for HMG-CoA reductaseJOURNAL OF MOLECULAR RECOGNITION, Issue 4 2008Valeriy V. Pak Abstract This study presents an approach that can be used to search for lead peptide candidates, including unconstrained structures in a recognized sequence. This approach was performed using the design of a competitive inhibitor for 3-hydroxy-3-methylglutaryl CoA reductase (HMGR). In a previous design for constrained peptides, a head-to-tail cyclic structure of peptide was used as a model of linear analog in searches for lead peptides with a structure close to an active conformation. Analysis of the conformational space occupied by the peptides suggests that an analogical approach can be applied for finding a lead peptide with an unconstrained structure in a recognized sequence via modeling a cycle using fixed residues of the peptide backbone. Using the space obtained by an analysis of the bioactive conformations of statins, eight cyclic peptides were selected for a peptide library based on the YVAE sequence as a recognized motif. For each cycle, the four models were assessed according to the design criterion ("V" parameter) applied for constrained peptides. Three cyclic peptides (FGYVAE, FPYVAE, and FFYVAE) were selected as lead cycles from the library. The linear FGYVAE peptide (IC50,=,0.4,µM) showed a 1200-fold increase the inhibitory activity compared to the first isolated LPYP peptide (IC50,=,484,µM) from soybean. Experimental analysis of the modeled peptide structures confirms the appropriateness of the proposed approach for the modeling of active conformations of peptides. Copyright © 2008 John Wiley & Sons, Ltd. [source] Study of the conformational profile of the norbornane analogues of phenylalanineJOURNAL OF PEPTIDE SCIENCE, Issue 6 2002Arnau Cordomí Abstract The conformational profile of the eight stereoisomeric 2-amino-3-phenylnorbornane-2-carboxylic acids (2-amino-3-phenylbicyclo[2.2.1]heptane-2-carboxylic acids) has been assessed by computational methods. These molecules constitute a series of four enantiomeric pairs that can be considered as rigid analogues of either L - or D -phenylalanine. The conformational space of their N -acetyl methylamide derivatives has been explored within the molecular mechanics framework, using the parm94 set of parameters of the AMBER force field. Local minimum energy conformations have been further investigated at the ab initio level by means of the Hartree-Fock and second order Moller-Plesset perturbation energy calculations using a 6,31G(d) basis set. The results of the present work suggest that the bulky norbornane structure induces two kinds of conformational constraints on the residues. On one hand, those of a steric nature directly imposed by the bicycle on the peptide backbone and, on the other hand, those that limit the orientations attainable by the phenyl ring which, in turn, reduces further the flexibility of the peptide backbone. A comparative analysis of the conformational profile of the phenylnorbornane amino acids with that of the norbornane amino acids devoid of the ,-phenyl substituent suggests that the norbornane system hampers the residue to adopt extended conformations in favour of C7-like structures. However, the bicycle itself does not impart a clear preference for any of the two possible C7 minima. It is the aromatic side chain, which is forced to adopt an almost eclipsed orientation, that breaks this symmetry introducing a marked preference for a single region of the (,, ,) conformational space in each of the phenylalanine norbornane analogues investigated. Copyright © 2002 European Peptide Society and John Wiley & Sons, Ltd. [source] Origin of Bends in Unperturbed Vinyl Polymers: An Illustration with PolystyreneMACROMOLECULAR THEORY AND SIMULATIONS, Issue 7 2007Yergou B. Tatek Abstract Previous experimental works have shown that dendronized vinyl polymers exhibit bends when adsorbed onto a surface. Two different mechanisms are believed to be responsible for the formation of these bends. These mechanisms are the temperature dependent random fluctuations of torsional bond states on one hand, and the intramolecular interactions due to the randomness in the stereochemical sequence of side chains on the other hand. Investigation of the amplitude and scope of the above mechanisms has been made by studying the conformational space of PS chains via RIS based Monte Carlo sampling. It was found that at low temperature bend formation is due to tacticity, whereas it was thermally driven at high temperature. The existence of a transition temperature between these two bend formation modes was demonstrated. It was also shown that for atactic chains, the maximum of bend formation occurs at Pm,,,0.7. [source] Accurate long-range distance measurements in a doubly spin-labeled protein by a four-pulse, double electron,electron resonance methodMAGNETIC RESONANCE IN CHEMISTRY, Issue 12 2008Michela G. Finiguerra Abstract Distance determination in disordered systems by a four-pulse double electron,electron resonance method (DEER or PELDOR) is becoming increasingly popular because long distances (several nanometers) and their distributions can be measured. From the distance distributions eventual heterogeneities and dynamics can be deduced. To make full use of the method, typical distance distributions for structurally well-defined systems are needed. Here, the structurally well-characterized protein azurin is investigated by attaching two (1-oxyl-2,2,5,5-tetramethylpyrroline-3-methyl) methanethiosulfonate spin labels (MTSL) by site-directed mutagenesis. Mutations at the surface sites of the protein Q12, K27, and N42 are combined in the double mutants Q12C/K27C and K27C/N42C. A distance of 4.3 nm is found for Q12C/K27C and 4.6 nm for K27C/N42C. For Q12C/K27C the width of the distribution (0.24 nm) is smaller than for the K27C/N42C mutant (0.36 nm). The shapes of the distributions are close to Gaussian. These distance distributions agree well with those derived from a model to determine the maximally accessible conformational space of the spin-label linker. Additionally, the expected distribution for the shorter distance variant Q12C/N42C was modeled. The width is larger than the calculated one for Q12C/K27C by 21%, revealing the effect of the different orientation and shorter distance. The widths and the shapes of the distributions are suited as a reference for two unperturbed MTSL labels at structurally well-defined sites. Copyright © 2008 John Wiley & Sons, Ltd. [source] Dynameomics: Large-scale assessment of native protein flexibilityPROTEIN SCIENCE, Issue 12 2008Noah C. Benson Abstract Structure is only the first step in understanding the interactions and functions of proteins. In this paper, we explore the flexibility of proteins across a broad database of over 250 solvated protein molecular dynamics simulations in water for an aggregate simulation time of ,6 ,s. These simulations are from our Dynameomics project, and these proteins represent approximately 75% of all known protein structures. We employ principal component analysis of the atomic coordinates over time to determine the primary axis and magnitude of the flexibility of each atom in a simulation. This technique gives us both a database of flexibility for many protein fold families and a compact visual representation of a particular protein's native-state conformational space, neither of which are available using experimental methods alone. These tools allow us to better understand the nature of protein motion and to describe its relationship to other structural and dynamical characteristics. In addition to reporting general properties of protein flexibility and detailing many dynamic motifs, we characterize the relationship between protein native-state flexibility and early events in thermal unfolding and show that flexibility predicts how a protein will begin to unfold. We provide evidence that fold families have conserved flexibility patterns, and family members who deviate from the conserved patterns have very low sequence identity. Finally, we examine novel aspects of highly inflexible loops that are as important to structural integrity as conventional secondary structure. These loops, which are difficult if not impossible to locate without dynamic data, may constitute new structural motifs. [source] Unfolding the fold of cyclic cysteine-rich peptidesPROTEIN SCIENCE, Issue 3 2008Amarda Shehu Abstract We propose a method to extensively characterize the native state ensemble of cyclic cysteine-rich peptides. The method uses minimal information, namely, amino acid sequence and cyclization, as a topological feature that characterizes the native state. The method does not assume a specific disulfide bond pairing for cysteines and allows the possibility of unpaired cysteines. A detailed view of the conformational space relevant for the native state is obtained through a hierarchic multi-resolution exploration. A crucial feature of the exploration is a geometric approach that efficiently generates a large number of distinct cyclic conformations independently of one another. A spatial and energetic analysis of the generated conformations associates a free-energy landscape to the explored conformational space. Application to three long cyclic peptides of different folds shows that the conformational ensembles and cysteine arrangements associated with free energy minima are fully consistent with available experimental data. The results provide a detailed analysis of the native state features of cyclic peptides that can be further tested in experiment. [source] Prediction of structures of multidomain proteins from structures of the individual domainsPROTEIN SCIENCE, Issue 2 2007Andrew M. Wollacott Abstract We describe the development of a method for assembling structures of multidomain proteins from structures of isolated domains. The method consists of an initial low-resolution search in which the conformational space of the domain linker is explored using the Rosetta de novo structure prediction method, followed by a high-resolution search in which all atoms are treated explicitly and backbone and side chain degrees of freedom are simultaneously optimized. The method recapitulates, often with very high accuracy, the structures of existing multidomain proteins. [source] Structure of a mutant T = 1 capsid of Sesbania mosaic virus: role of water molecules in capsid architecture and integrityACTA CRYSTALLOGRAPHICA SECTION D, Issue 10 2005V. Sangita Deletion of the N-terminal 31 amino acids from the coat protein (CP) of Sesbania mosaic virus (SeMV) results in the formation of T = 1 capsids. The X-ray crystal structure of CP-N,31 mutant capsids reveals that the CP adopts a conformation similar to those of other T = 1 mutants. The 40 N-terminal residues are disordered in CP-N,31. The intersubunit hydrogen bonds closely resemble those of the native capsid. The role of water molecules in the SeMV structure has been analyzed for the first time using the present structure. As many as 139 of the 173 waters per subunit make direct contacts with the protein atoms. The water molecules form a robust scaffold around the capsid, stabilize the loops and provide integrity to the subunit. These waters constitute a network connecting diametrically opposite ends of the subunit. Such waters might act as nodes for conveying signals for assembly or disassembly across a large conformational space. Many water-mediated interactions are observed at various interfaces. The twofold interface, which has the smallest number of protein,protein contacts, is primarily held by water-mediated interactions. The present structure illuminates the role of water molecules in the structure and stability of the capsid and points out their possible significance in assembly. [source] Analysis of quinazoline and pyrido[2,3- d]pyrimidine N9,C10 reversed-bridge antifolates in complex with NADP+ and Pneumocystis carinii dihydrofolate reductaseACTA CRYSTALLOGRAPHICA SECTION D, Issue 9 2002Vivian Cody Structural studies of two ternary complexes of Pneumocystis carinii dihydrofolate reductase (pcDHFR) with the cofactor NADP+ and potent antifolates, the N9,C10 reversed-bridge inhibitor 2,4-diamino-6-[N -(2,,5,-dimethoxybenzyl)- N -methylamino]quinazoline (1) and its 3,,5,-dimethoxypyrido[2,3- d]pyrimidine analog (2), were carried out. Data for the monoclinic crystals were refined to 1.90,Å resolution for the complex with (1) (R = 0.178) and to 2.1,Å resolution for the complex with (2) (R = 0.193). The effect of the N9,C10 reversed-bridge geometry is to distort the bridge from coplanarity with the pyrido[2,3- d]pyrimidine or quinazoline ring system and to twist the C10 methylene conformation toward a gauche conformation. This change also influences the conformation of the methoxybenzyl ring, moving it away from a trans position. This change places the 5,-methoxy group deeper within the hydrophobic pocket made by Ile65, Pro66 and Phe69 of the pcDHFR active site. These results also revealed the first observation of an unusual conformation for the reversed-bridge geometry (C5,C6,N9,C10 torsion angle) in antifolate (2). The electron density is consistent with the presence of two models (conformers 2-1 and 2-2) that result from inversion of the geometry at N9. The four examples of N9,C10 reversed-bridge antifolates cluster in two conformations, with the structure of quinazoline (1) similar to that previously reported for its 2,,5,-dimethoxypyrido[2,3- d]pyrimidine analog (3). The two conformers of (2) differ from these and each other by a twisted-bridge geometry that results in the dimethoxybenzyl ring occupying the same conformational space. Conformer 2-2 also has the N9,C10 reversed bridge perpendicular to the pyrido[2,3- d]pyrimidine plane, in contrast to the gauche,trans conformation normally observed. As a result of these changes, the N9 methyl probes conformational space in the active site not normally occupied by antifolate structures. The N9 methyl of conformer 2-2 makes close contacts to the conserved Leu25 as well as the hydroxyl O atoms of the nicotinamide ribose and Ser64, whereas the other three reversed-bridge conformers make weak hydrophobic contacts with Ile123, Thr61 and Ile65. These antifolates are ten times more selective for pcDHFR than the C9,N10 bridge parent trimetrexate. However, pyrido[2,3- d]pyrimidines (2) and (3) are three times more selective for pcDHFR than quinazoline (1) is for rat liver DHFR. These data suggest that the loss of hydrogen-bonding interactions with N8 is more important to potency than the interactions of the methoxybenzyl substituents. [source] Starch phosphorylation,Maltosidic restrains upon 3,- and 6,-phosphorylation investigated by chemical synthesis, molecular dynamics and NMR spectroscopyBIOPOLYMERS, Issue 3 2009Peter I. Hansen Abstract Phosphorylation is the only known in vivo substitution of starch, yet no structural evidence has been provided to explain its implications of the amylosidic backbone and its stimulating effects on starch degradation in plants. In this study, we provide evidence for a major influence on the glucosidic bond in starch specifically induced by the 3-O-phosphate. Two phosphorylated maltose model compounds were synthesized and subjected to combined molecular dynamics (MD) studies and 950 MHz NMR studies. The two phosphorylated disaccharides represent the two possible phosphorylation sites observed in natural starches, namely maltose phosphorylated at the 3,- and 6,-position (maltose-3,-O-phosphate and maltose-6,-O-phosphate). When compared with maltose, both of the maltose-phosphates exhibit a restricted conformational space of the ,(1,4) glycosidic linkage. When maltose is phosphorylated in the 3,-position, MD and NMR show that the glucosidic space is seriously restricted to one narrow potential energy well which is strongly offset from the global potential energy well of maltose and almost 50°degrees from the , angle of the ,-maltose crystal structure. The driving force is primarily steric, but the configuration of the structural waters is also significantly altered. Both the favored conformation of the maltose-3,-phosphate and the maltose-6,-phosphate align well into the 6-fold double helical structure of amylopectin when the effects on the glucosidic bond are not taken into account. However, the restrained geometry of the glucosidic linkage of maltose-3,-phosphate cannot be accommodated in the helical structure, suggesting a major local disturbing effect, if present in the starch granule semi-crystalline lattice. © 2008 Wiley Periodicals, Inc. Biopolymers 91: 179,193, 2009. This article was originally published online as an accepted preprint. The "Published Online" date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com [source] BINOL-3,3,-Triflone N,N -Dimethyl Phosphoramidites: Through-Space 19F,31P Spin,Spin Coupling with a Remarkable Dependency on Temperature and Solvent Internal PressureCHEMISTRY - A EUROPEAN JOURNAL, Issue 26 2008Matthias Kruck Abstract A combined computational and experimental study of the effects of solvent, temperature and stereochemistry on the magnitude of the through-space spin,spin coupling between 31P and 19F nuclei which are six-bonds apart is described. The reaction of 3-trifluoromethylsulfonyl-2,,2-dihydroxy-1,1,-binaphthalene (3-SO2CF3 -BINOL) with hexamethylphosphorous triamide (P(NMe2)3) generates a pair of N,N -dimethylphosphoramidites which are diastereomeric due to their differing relative configurations at the stereogenic phosphorous centre and the axially chiral (atropisomeric) BINOL unit. Through-space NMR coupling of the 31P and 19F nuclei of the phosphoramidite and sulfone is detected in one diastereomer only. In the analogous N,N -dimethylphosphoramidite generated from 3,3,-(SO2CF3)2 -BINOL only one of the diastereotopic trifluoromethylsulfone moieties couples with the 31P of the phosphoramidite. In both cases, the magnitude of the coupling is strongly modulated (up to 400,%) by solvent and temperature. A detailed DFT analysis of the response of the coupling to the orientation of the CF3 moiety with respect to the P-lone pair facilitates a confident assignment of the stereochemical identity of the pair of diastereomers. The analysis shows that the intriguing effects of environment on the magnitude of the coupling can be rationalised by a complex interplay of solvent internal pressure, molecular volume and thermal access to a wider conformational space. These phenomena suggest the possibility for the design of sensitive molecular probes for local environment that can be addressed via through-space NMR coupling. [source] Musings on ADME Predictions and Structure,Activity RelationsCHEMISTRY & BIODIVERSITY, Issue 11 2005Bernard Testa The first part of the paper examines Structure,Activity Relations (SARs) and their components from a very general point of view. The various types of interpretation emerging from statistically valid relations will be examined, namely causal (mechanistic), contextual (empirical), fortuitous, and tautological correlations. Implications for ADME predictions will be seen when discussing the diversity of interactions between active compounds (e.g., drugs) and biological systems. The second part of the paper is more specific and presents the concept of molecular-property space, an all but neglected concept in SARs. Recent results from Molecular Dynamics (MD) simulations and Molecular Interaction Fields (MIF) computations of acetylcholine will be used to illustrate not only the well-known conformational space of this molecule, but also its property space as exemplified by its lipophilicity space. It will be seen that a molecule as small as acetylcholine is able to span a relatively broad property space. Most significantly in an ADME perspective, the molecule is able, within the limits of its property space, to adapt to the medium. This is equivalent to saying that the medium constrains the molecule to resemble it as much as feasible. [source] Solvent effects on the conformational distribution and optical rotation of ,-methyl paraconic acids and esters,CHIRALITY, Issue 5 2006S. Coriani Abstract A computational investigation of the optical rotatory power of cis and trans 2-methyl-5-oxo-tetrahydro-3-furancarboxylic acids and the corresponding methyl and ethyl esters is presented. Solvent effects on both the conformational space and the rotatory power are analyzed by comparing results obtained in vacuo with those computed,using the Polarizable Continuum Model,in methanol. A comparison with experimental observations for the optical rotatory power of the title compounds in methanol is also carried out, in a few cases also for several wavelengths. Agreement between theory and experiment is in all cases excellent, in particular when solvent effects are included both in the geometry optimization and in the calculation of the OR, thus confirming the validity of the computational procedure adopted, even for this challenging family of floppy molecules. Chirality, 2006. © 2006 Wiley-Liss, Inc. [source] Complete maps of molecular-loop conformational spacesJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 1 2008Josep M. Porta First page of article [source] Conformational analysis by intersection: CONANJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 1 2003Andrew Smellie Abstract As high throughput techniques in chemical synthesis and screening improve, more demands are placed on computer assisted design and virtual screening. Many of these computational methods require one or more three-dimensional conformations for molecules, creating a demand for a conformational analysis tool that can rapidly and robustly cover the low-energy conformational spaces of small molecules. A new algorithm of intersection is presented here, which quickly generates (on average <0.5 seconds/stereoisomer) a complete description of the low energy conformational space of a small molecule. The molecule is first decomposed into nonoverlapping nodes N (usually rings) and overlapping paths P with conformations (N and P) generated in an offline process. In a second step the node and path data are combined to form distinct conformers of the molecule. Finally, heuristics are applied after intersection to generate a small representative collection of conformations that span the conformational space. In a study of ,97,000 randomly selected molecules from the MDDR, results are presented that explore these conformations and their ability to cover low-energy conformational space. © 2002 Wiley Periodicals, Inc. J Comput Chem 24: 10,20, 2003 [source] Conformational spaces of the gastrointestinal antisecretory chiral drug omeprazole: Stereochemistry and tautomerismCHIRALITY, Issue 1 2006Hava Caner Abstract A study of the conformational spaces of the chiral proton pump inhibitor (PPI) drug omeprazole by semiempirical, ab-initio, and DFT methods is described. In addition to the chiral center at the sulfinyl sulfur atom, the chiral axis at the pyridine ring (due to the hindered rotation of the 4-methoxy substituents) was considered. The results were analyzed in terms of the 5-methoxy and 6-methoxy tautomers and the two pairs of enantiomers (R,P)/(S,M) and (R,M)/(S,P). Five torsion angles were systematically explored: the backbone rotations defined by D1 (N3,C2,S10,O11), D2 (C2,S10,C12,C13), and D3 (S10,C12,C13,N14) and two methoxy rotations defined by D4 (C6,C5,O8,C9) and D5 (C16,C17,O19,C20). Significant energy differences were revealed between the 5- and 6-methoxy tautomers, the extended and folded conformations, and the (S,M) and (S,P) diastereomers. The "extended M" conformation of the 6-methoxy tautomer of (S)-omeprazole was found to be the most stable conformer. © 2005 Wiley-Liss, Inc. Chirality [source] | ||||||||||