A CoMFA analysis with conformational propensity: An attempt to analyze the SAR of a set of molecules with different conformational flexibility using a 3D-QSAR method

CoMFA analysis, a widely used 3D-QSAR method, has limitations to handle a set of SAR data containing diverse conformational flexibility since it does not explicitly include the conformational entropic effects into the analysis. Here, we present an attempt to incorporate the conformational entropy effects of a molecule into a 3D-QSAR analysis. Our attempt is based on the assumption that the conformational entropic loss of a ligand upon making a ligand-receptor complex is small if the ligand in an unbound state has a conformational propensity to adopt an active conformation in a complex state. For a QSAR analysis, this assumption was interpreted as follows: a potent ligand should have a higher conformational propensity to adopt an `active-conformation'-like structure in an unbound state than an inactive one. The conformational propensity value was defined as the populational ratio, N<sub>active</sub>/N<sub>stable</sub>, of the number of energetically stable conformers, N<sub>stable</sub>, to the number of `active-conformation'-like structures, N_active. The latter number was calculated by counting the number of conformers that satisfied the structural parameters deduced from the active conformation. A set of SAR data of imidazoleglycerol phosphate dehydratase inhibitors containing 20 molecules with different conformational flexibility was used as a training set for developing a 3D structure-activity relationship by a CoMFA analysis with the conformational propensity value. This resulted in a cross-validated squared correlation coefficient of the CoMFA model with the conformational propensity value (R ² _cross = 0.640) higher than that of the standard CoMFA model (R ² _cross = 0.431). Then we evaluated the quality of the CoMFA models by predicting the inhibitory activity for a new molecule.     

A CGenFF-based force field for simulations of peptoids with both cis and trans peptide bonds

Peptoids, or poly-n-substituted glycines, are peptide-like polymers composed of a flexible backbone decorated with diverse chemical side chains. Peptoids can form a variety of self-assembling structures based on the type and sequence of the side chains attached to their backbones. All-atom molecular dynamics simulations have been useful in predicting the conformational structures of proteins and will be valuable tools for identifying combinations of peptoid side chains that may form interesting folded structures. However, peptoid models must address a major degree of freedom not common in proteins – the cis/trans isomerization of the peptide bond. This work presents CHARMM general force field (CGenFF) parameters developed to accurately represent peptoid conformational behavior, with an emphasis on a correct representation of both the cis and trans isomers of the peptoid backbone. These parameters are validated against experimental and quantum mechanics data and used to simulate three peptoid side chains in explicitly solvated systems. © 2019 Wiley Periodicals, Inc.     

Rigorous Conformational Analysis of Pyrrolidine Enamines with Relevance to Organocatalysis

It has been suggested that the origin of regio‐ and stereoselectivity in Michael additions of pyrrolidine enamines is achieved by thermodynamic rather than kinetic control through distinct conformational preferences of the enamines. We assess this proposal by elaboration of a computational protocol that warrants sufficient accuracy. The small energy differences between the conformers necessitate a high accuracy of the electronic structure method which, in addition, must allow for computationally feasible calculations of a large number of conformers. Our protocol is based on density functional theory which we validated against explicitly correlated coupled cluster theory. The results are in agreement with the available experimental data, but illustrate that conformational preferences determined for one enamine are not readily transferable to other types of enamines. We found that an appropriate conformational sampling is inevitable to arrive at meaningful conclusions. Most prominently, s‐cis and s‐trans conformers are similarly stable for aldehyde‐ and ketone‐derived enamines. The regio‐ and stereoselectivity in Michael additions of pyrrolidine‐derived enamines can not be explained by pronounced stability differences of the enamine isomers and conformers in general, disproving the thermodynamic‐control hypothesis. The elucidation of the origin of regio‐ and stereoselectivity requires further theoretical investigations of the elementary steps of Michael additions.     

Angular Alkylation of cis-Decalin Epoxides with C-nucleophiles: Mechanism,scope, and limitations of a novel bridgehead functionalisation

The angular alkylation of cis-decalin epoxides like 5 or 7 can be achieved at C(8a)

1 For convenience, the arbitrary numbering given for 5 (Scheme I) is used throughout the General Part; for systematic names, see Exper. Part.

in good yield by using CuI and a large excess of Grignard reagents without an sp³ centre at C(2). The reaction proceeds via a carbenium-ion intermediate which is stabilised by homoconjugative interaction with the adjacent double bond. Due to 1,3-diaxial strain in the alkoxides resulting from alkylation or reduction at C(4a) of the epoxides 5 or 7 , the nucleophile is delivered selectively to C(8a). Grignard reagents possessing H-atoms at C(β), transfer a hydride to the epoxide yielding the trans-decalol 11 (Grignard reduction). The angular alkylation of 5 with allylic and benzylic Grignard reagents proceeds with good yield.     

On Cardioactive Steroids. VIII. The Synthesis of Bufalin and Resibufogenin Isomers

α-Isobufalin

1 Systematic names are given at the titles of the Exper. Part.

( 1 ) and β-isoresibufogenin ( 3 ) have been synthesized from testosterone by a method which features a novel oxidative furan to pyrone transformation.     

Conformational Modularity of an Abiotic Secondary‐Structure Motif in Aqueous Solution

We have investigated an abiotic secondary structure based on the stacking of alternating electron‐rich (1,5‐dialkoxynaphthalene (Dan)) and electron‐deficient (1,4,5,8‐naphthalene‐tetracarboxylic diimide (Ndi)=benzo[lmn][3,8]phenanthroline‐1,3,6,8(2H,7H)‐tetrone) aromatic units. Previously, the specifics of conformational behavior were uncovered in the minimal folding unit, namely the dimer, consisting of one Dan and one Ndi unit linked through various amino acid residues. Here is reported the investigation of a series of larger oligomers (trimers and tetramers) composed of selected dimer units. We determined that some of the larger oligomers displayed conformational modularity, that is, the persistence of subunit‐conformational propensities when those subunits were used as components of larger structures. Conformational modularity can be viewed as a desirable property of folding molecules because it simplifies not only the design of larger, more complex oligomers, but also the structural analyses of such species.     

Conformational analysis of a secondary hydroxamic acid in aqueous solution by NOE spectroscopy

Hydroxamic acids are metal‐binding compounds used by micro‐organisms and possess applications in medicine and industry. Hydroxamic acids favor two conformations, E and Z; metal binding is limited to the Z conformation. The Z conformation may be identifiable by NOE spectroscopy, but analysis is complicated by the potential for long‐range coupling as well as for relayed NOEs due to conformational switching. In this report, we re‐examine the reported conformational preference of N‐methyl acetohydroxamic acid (NMHA) in D₂O using NOE spectroscopy. We find that the favored conformation of NMHA in aqueous solution is the E conformation, contrary to an earlier report. NOE build‐up curves are proposed as a valuable tool to probe conformational behavior in similar systems. Copyright © 2013 John Wiley & Sons, Ltd.     

Organic Stereochemistry. Part 7

This review continues a general presentation of the principles of stereochemistry with special emphasis on the biomedicinal sciences. Here, we discuss and illustrate the phenomenon of substrate stereoselectivity in biochemistry (endogenous metabolism) and principally in xenobiochemistry or drug metabolism. The review begins with an overview of the stereoselective processes occurring in the biomedicinal sciences. The general rule is for distinct stereoisomers, be they enantiomers or diastereoisomers, to elicit different pharmacological responses (Part 5), to a lesser extent be transported with different efficacies (Part 5), and to be metabolized at different rates (this Part). In other words, biological environments discriminate between stereoisomers both when acting on them and when being acted upon by them. The concept of substrate stereoselectivity describes this phenomenon in endogenous biochemistry and xenobiotic metabolism, as discussed and illustrated in the present Part. The sister concept of product stereoselectivity will be presented in Part 8.     

Conformational analysis of 2-methyl-1,3,2-oxaza- and 2-methyl-1,3,2-oxathiaborinane associates with water molecule

The structure and conformational behavior of 1: 1 molecular assotsiates of 2-methyl-1,3,2-oxazaand 2-methyl-1,3,2-oxathiaborinanes with water were studied ab initio in terms of HF/6-31G(d) and PBE/3z quantum-chemical approximations. The most stable complexes are formed via hydrogen bonding with the heteroatoms (oxygen and nitrogen or sulfur). Their conformational behavior implies equilibrium between sofa and half-chair conformers, and intermolecular hydrogen bond is retained in the course of ring interconversion. No associate with a dative O→B bond is formed.     

Modification of Cyclosporin A (CS): Generation of an enolate at the sarcosine residue and reactions with electrophiles

Strong bases (lithium diisopropylamide (LDA) or BuLi) convert cyclosporin A (CS) to hexalithio derivative containing a Li alkoxide, four Li azaenolate, and one Li enolate units. The Li₆ compound is solubilized in tetrahydrofuran (THF) by addition of excess LDA or LiCl. Reactions with electrophiles (alkyl halides, aldehydes, ClCO₂R, CO₂, (RS)₂, D₂O) at low temperatures give products containing new side chains in amino-acid residue 3 of the cyclic undecapeptide (see 1 – 13 , Schemes 1, and 2, and Figs. 1 and 2) in moderate to high yields and, with Re- or Si-selectivities, depending upon the conditions of lithiation of up to 7:1, Pure CS derivatives (Scheme 2, Table 1 in the Exper. Part) can be isolated by column chromatography. N-Alkylations or cleavage of the peptide backbone by carbonyl addition occur only at higher temperatures and/or with prolonged reaction times (see 14 and 15 in Scheme 4). Very little or no epimerization of stereogenic centers occurs under the conditions employed. Possible reasons for the feasibility of these surprizing conversions of CS are discussed (Schemes 4 and 5 and Fig. 3). For comparision, [MeAla³]CS ( 2b ) and [D -MeAla³]CS ( 2a ) were also prepared by conventional peptide synthesis in solution (Schemes 6 and 7). Their ¹H- and ¹³C-NMR spectra are compared with those of CS (Table 2 in the Exper. Part).     

Rigid backbone polymers. I. Polyisocyanides

Concentrated solutions of poly(n-octyl isocyanide) exhibit a mesomorphic structure, most probably nematic in nature. Poly(n-butyl isocyanide) and poly(benzyl isocyanide), of the molecular weights at our disposal, failed to show similar behavior. Upon acidification poly(n-butyl isocyanide) does not change, but the other two polymers turn essentially black. Infrared and proton NMR clearly demonstrate that upon acidification, poly(n-butyl isocyanide) and poly(benzyl isocyanide) are protonated on the nitrogen atom. This process is reversible. Carbon-13 NMR and x-ray patterns indicate that no chemical rearrangement or conformational changes take place upon acidification. This conclusion is supported by infrared studies and by inference from the poor electrical conductivity of the solid acidified polymers.     

Synthesis and Properties of Conformationally Constrained Analogues of Floral‐Type Odorants

The twelve bridged analogues 8 – 19 of floral‐type odorants related to cyclamenaldehyde ( 1 ) were synthesized (Schemes 1–5) to investigate the relationship between the structural and conformational features of these compounds and their odor properties. Comparison of the data from sensory evaluation and molecular modeling suggests that the side chain of both the unconstrained and the constrained active analogues is not extended (anti) but rather folded (gauche) in the ‘bioactive’ conformation. However, it is mainly the nature of the substituents at the α position of the aldehyde function that critically influences the odor quality and strength. These studies provide new information that should aid ongoing efforts to develop models of odorant? receptor interactions.     

Conformational Preferences of a β‐Octapeptide as Function of Solvent and Force‐Field Parameters

The ability to design properly folded β‐peptides with specific biological activities requires detailed insight into the relationship between the amino acid sequence and the secondary and/or tertiary structure of the peptide. One of the most frequently used spectroscopic techniques for resolving the structure of a biomolecule is NMR spectroscopy. Because only signal intensities and frequencies are recorded in the experiment, a conformational interpretation of the recorded data is not straightforward, especially for flexible molecules. The occurrence of conformational and/or time averaging, and the limited amount and accuracy of experimental data hamper the precise conformational determination of a biomolecule. In addition, the relation between experimental observables with the underlying conformational ensemble is often only approximately known, thereby aggravating the difficulty of structure determination of biomolecules. The problematic aspects of structure refinement based on NMR nuclear Overhauser effect (NOE) intensities and ³J‐coupling data are illustrated by simulating a β‐octapeptide in explicit MeOH and H₂O as solvents using three different force fields. NMR Data indicated that this peptide would fold into a 3₁₄‐helix in MeOH and into a hairpin in H₂O. Our analysis focused on the conformational space visited by the peptide, on structural properties of the peptide, and on agreement of the MD trajectories with available NMR data. We conclude that 1) although the 3₁₄‐helical structure is present when the peptide is solvated in MeOH, it is not the only relevant conformation, and that 2) the NMR data set available for the peptide, when solvated in H₂O, does not provide sufficient information to derive a single secondary structure, but rather a multitude of folds that fulfill the NOE data set.     

NMR Investigation of the Influence of Sulfate Groups at C‐2 and C‐4 on the Conformational Behavior of Fucoidan Fragments with Homo‐(1→3)‐Linked Backbone#

The conformational behavior of 2‐O‐ and 4‐O‐sulfated derivatives of linear (1→3)‐linked di‐, tri‐, and tetrafucosides and 2,3‐branched tetrafucoside was studied by means of theoretical molecular modeling and experimental determination of trans‐glycosidic vicinal coupling constants ³J_C,H. It was shown that O‐sulfation of (1→3)‐linked oligofucosides restricts their conformational flexibility and changes the conformational equilibrium if compared with the parent nonsulfated oligosaccharides. In the case of 2‐O‐sulfated oligofucosides, the conformations of O‐glycoside linkages depend on its location within the oligosaccharide chain and the chain length as well as on the presence of a 2,3‐branch, whereas the conformation of the (1→3)‐linkage in the presence of a 4‐O‐sulfate group only depends on the presence of a 2,3‐branch.     

Conformational Analysis and Selection of Odor‐Active Conformers: Synthesis of Molecules Designed for the Lily‐of‐the‐Valley(Muguet)‐Type Odor

The selection of odor‐active conformers and the construction of a model for a targeted odor type, i.e., for the lily‐of‐the‐valley odor, were examined. The disagreement of the odors of 1,3,4,5‐tetrahydro‐2‐benzoxepin derivative 1 and 3‐[4‐(tert‐butyl)phenyl]‐2‐methylpropanal ( 2 ) is discussed in terms of their stable conformers. The conformer active for the lily‐of‐the‐valley odor was investigated by conformational analyses of several related compounds. Based on the integrated model consisting of the assumed active conformers (Fig. 5), compounds anticipated to possess the lily‐of‐the‐valley odor were designed and synthesized. The odor of synthetic 7‐(tert‐butyl)‐1,2,4,5‐tetrahydro‐3H‐benzocyclohepten‐3‐one ( 8 ) and 3‐[4‐(tert‐butyl)phenyl]cyclopentanone ( 13 ) were evaluated by perfumers to have a floral odor and to recall the lily‐of‐the‐valley and lilac odors, respectively. Our methodology to design new odoriferous compounds, based on conformational analysis, selection of odor‐active conformers, and construction of a model, proved to be satisfactory.     

Direct and mediated electron transfer catalyzed by anionic tobacco peroxidase

The properties of anionic tobacco peroxidase (TOP) adsorbed on graphite electrode have been studied in direct and mediated electron transfer in a wall-jet flow injection system. The percentage of tobacco peroxidase molecules active in directelectron transfer is about 83%, which is higher than that for horeradish peroxidase (40–50%). This observation is explained in terms of the lower degree of glycosylation of TOP compared with horseradish peroxidase and, therefore, a reduced in terference from the oligosaccharide chains with direct electron transfer. Calcium ions cause an 11% drop in the reaction rate constant toward hydrogen peroxide. The detection limit of calcium chloride has been estimated as 5 m M. The results obtained by means of bioeletrochemistry, stopped-flow kinetics, and structural modeling provide evidence for the interaction between calcium cations and negatively charged residues at the distal domain (Glu-141, heme propionates, Asp-79, Asp-80) blocking the activesite. The observation that both soluble and immobilized enzyme under go conformational changes resulting in the blockade of the active site indicates that the immobilized enzyme preserves conformational flexibility. An even stronger suppressing effect of calcium ions on the rate constant for mediated electron transfer was observed. In the case of direct electron transfer, this couldmean that there is nodirect contact between the electrode and the active site of TOP. The electrons are shuttled from the active site to the surface of the electrode through electron transfer pathways in the protein globule that are sensitive to protein conformational changes.     

Physical ageing in poly(vinyl acetate) 1. Enthalpy relaxation

The enthalpy changes ΔH_∞ between a poly(vinyl acetate) glass formed by rapid cooling and the corresponding fully relaxed glass have been estimated at four temperatures below the glass transition. The values obtained were different to those expected by extrapolating liquid behavior below the glass transition and were found to agree well with the predictions of a simple expression for the combined main chain conformational and free volume contributions to enthalpy. Conformational contributions from the side chain alone were also considered but were not required to obtain agreement with experiment. It can be concluded that the side chains remained mobile below the glass transition and do not contribute to the heat capacity discontinuity at T_g. © 1997 John Wiley & Sons, Inc. J Polym Sci B: Polym Phys 35: 1107–1116, 1997     

Substituted N-cyanomethyl-2-halo-N-methylarenecarboxamides as precursors of 1,4-benzothiazepines

2-Halogeno substituted N-cyanomethyl-N-methylbenzamides 1a-1i were investigated in a correlation analysis by ir spectroscopy to determine the conformational behavior. Compound 1h gives 4-methyl-2-methylthio-8-nitro-5-oxo-4,5-dihydro-1,4-benzothiazepine-3-carbonitrile 3 by dithiocarboxylation procedure whereas 1b was not able to react to heterocyclic seven-membered ring system.     

New optimization method for conformational energy calculations on polypeptides: Conformational space annealing

A new optimization method is presented to search for the global minimum-energy conformations of polypeptides. The method combines essential aspects of the build-up procedure and the genetic algorithm, and it introduces the important concept of “conformational space annealing.” Instead of considering a single conformation, attention is focused on a population of conformations while new conformations are obtained by modifying a “seed conformation.” The annealing is carried out by introducing a distance cutoff, D_cut, which is defined in the conformational space; D_cut effectively divides the whole conformational space of local minima into subdivisions. The value of D_cut is set to a large number at the beginning of the algorithm to cover the whole conformational space, and annealing is achieved by slowly reducing it. Many distinct local minima designed to be distributed as far apart as possible in conformational space are investigated simultaneously. Therefore, the new method finds not only the global minimum-energy conformation but also many other distinct local minima as by-products. The method is tested on Met-enkephalin, a 24-dihedral angle problem. For all 100 independent runs, the accepted global minimum-energy conformation was obtained after about 2600 minimizations on average. © 1997 John Wiley & Sons, Inc. J Comput Chem 18: 1222–1232