Marcin Hoffmann

Factors Affecting Conformation of (R,R)-Tartaric Acid Ester, Amide and Nitrile Derivatives. X-Ray Diffraction, Circular Dichroism, Nuclear Magnetic Resonance and Ab Initio Studies

Abstract Derivatives 2a–15a of (R,R)-tartaric acid (1a) with all combinations of methyl ester, amide, N-methylamide and N,N-dimethylamide groups, as well as the corresponding O,O′-dibenzoyl derivatives 1b–15b and nitriles 16–18 have been synthesized. Their conformations have been studied by the NMR and CD methods in solution as well as by X-ray diffraction in the crystalline state. The preference for planar. T conformation of the four carbon chain is observed under conditions restricting the α-hydroxyacid, ester or amide group to be nearly planar, this conformation being stabilized by intramolecular hydrogen bonds of the S(5) motif and the electrostatic CO/C(β)H and CN/C(β)H coplanar bond interactions. The C=O/C(α)-O bond system tends to be either synplanar (ester, acid), or antiplanar (ester, primary and secondary amide). Ab initio calculations allowed to demonstrate that for the isolated molecules of diamides 10a and 15a there is strong preference for gauche G+(a,a) conformers, the driving force being the formation of the hydrogen bonded six-membered cycles of the S(6) motif joining the OH and C=O groups from two different halves of the molecule. The results compare favourably with the experimental values derived from NMR spectra of 15a in nonpolar solvent. In the absence of intramolecular hydrogen bonding the N,N-dimethylamide group is better accomodated in a gauche G− conformer. This releases the nonbonded interaction due to the amide methyl group anti to the carbonyl group.

Toward a Physical Interpretation of Substituent Effects: The Case of Fluorine and Trifluoromethyl Groups

The application of ab initio and DFT computational methods at six different levels of theory (MP2/cc-pVDZ, MP2/aug-cc-pVTZ, B3LYP/cc-pVDZ, B3LYP/aug-cc-pVTZ, M06/cc-pVDZ, and M06/aug-cc-pVTZ) to meta- and para-substituted fluoro- and trifluoromethylbenzene derivatives and to 1-fluoro- and 1-trifluoromethyl-2-substituted trans-ethenes allowed the study of changes in the electronic and geometric properties of F- and CF3-substituted systems under the impact of other substituents (BeH, BF2, BH2, Br, CFO, CHO, Cl, CN, F, Li, NH2, NMe2, NO, NO2, OH, H, CF3, and CH3). Various parameters of these systems have been investigated, including homodesmotic reactions in terms of the substituent effect stabilization energy (SESE), the π and σ electron donor-acceptor indexes (pEDA and sEDA, respectively), the charge on the substituent active region (cSAR, known earlier as qSAR), and bond lengths, which have been regressed against Hammett constants, resulting mostly in an accurate correspondence except in the case of p-fluorobenzene derivatives. Moreover, changes in the characteristics of the ability of the substituent to attract or donate electrons under the impact of the kind of moiety to which the substituent is attached have been considered as the indirect substituent effect and investigated by means of the cSAR model. Regressions of cSAR(X) versus cSAR(Y) for any systems X and Y allow final results to be obtained on the same scale of magnitude.

Detailed Mechanism of Squalene Epoxidase Inhibition by Terbinafine

Squalene epoxidase (SE) is a key flavin adenine dinucleotide (FAD)-dependent enzyme of ergosterol and cholesterol biosynthetic pathways and an attractive potential target for drugs used to inhibit the growth of pathogenic fungi or to lower cholesterol level. Although many studies on allylamine drugs activity have been published during the last 30 years, up until now no detailed mechanism of the squalene epoxidase inhibition has been presented. Our study brings such a model at atomic resolution in the case of yeast Saccharomyces cerevisiae . Presented data resulting from modeling studies are in excellent agreement with experimental findings. A fully atomic three-dimensional (3D) model of squalene epoxidase (EC 1.14.99.7) from S. cerevisiae was built with the help of 3D-Jury approach and further screened based on data known from mutation experiments leading to terbinafine resistance. Docking studies followed by molecular dynamics simulations and quantum interaction energy calculations [MP2/6-31G(d)] resulted in the identification of the terbinafine-squalene epoxidase mode of interaction. In the energetically most likely orientation of terbinafine its interaction energy with the protein is ca. 120 kJ/mol. In the favorable position the terbinafine lipophilic moiety is located vertically inside the squalene epoxidase binding pocket with the tert-butyl group oriented toward its center. Such a position results in the SE conformational changes and prevents the natural substrate from being able to bind to the enzymes active site. That would explain the noncompetitive manner of SE inhibition. We found that the strongest interaction between terbinafine and SE stems from hydrogen bonding between hydrogen-bond donors, hydroxyl group of Tyr90 and amine nitrogen atom of terbinafine. Moreover, strong attractive interactions were recorded for amino acids whose mutations resulted in terbinafine resistance. Our results, elucidating at a molecular level the mode of terbinafine inhibitory activity, can be utilized in designing more potent or selective antifungal drugs or even medicines lowering cholesterol in humans.

(R,R)-Tartaric Acid Dimethyl Diester from X-Ray and Ab Initio Studies: Factors Influencing Its Conformation and Packing

The conformation of dimethyl (R,R)-tartrate has been analyzed on the basis of the single crystal X-ray diffraction method as well as by ab-initio quantum chemical studies. The results showed that the extended T conformation containing two planar hydroxyester moieties predominates in both ab-initio and X-ray studies. The lowest energy conformer in ab-initio calculations has C2 symmetry and hydrogen bonds between a hydroxyl group and the nearest carbonyl oxygen. The second in energetical sequence, with an energy difference of only 1.2 kcal/mol, is the asymmetrical conformer, which differs from the lowest energy form by the rotation of one of the ester groups by 180°. Intramolecular OH...O hydrogen bonds observed in this rotamer again involve only proximal functional groups. This conformer is present in the crystal structure of the studied compound, although its conformation in the solid state is no longer stabilized by intramolecular hydrogen bonds of the type mentioned above. In the crystal, hydroxyl groups are mostly involved in intermolecular hydrogen bonds and form only a weak intramolecular hydrogen bond with each other. The planar arrangement of the α-hydroxyester moieties combined with the extended conformation of the carbon chain seems to be stabilized by the intramolecular hydrogen bonds between neighboring functional groups and by the long range dipole-dipole interactions between two pairs of CO and (β)C-H bonds.

DFT study on hydroxy acid–lactone interconversion of statins: the case of fluvastatin

Fluvastatin is a member of the HMG-CoA reductase inhibitor family of drugs, commonly referred to as statins. It is generally known that, under physiological conditions, statins are susceptible to pH-dependent interconversion between their active (hydroxy acid) and inactive (lactone) forms. The mechanism of this interconversion, under both acidic and basic conditions, was investigated theoretically using the density functional theory (DFT) method. Regardless of the conditions, the lactone form was always higher in energy by 6-19 kcal mol(-1). However, under basic conditions, the activation barrier for the hydrolysis was significantly lower (9 kcal mol(-1)) than for the reverse reaction (28 kcal mol(-1)), making the lactone form unstable. The activation barriers under acidic conditions were of comparable height in both directions (22 and 28 kcal mol(-1)), making the occurrence of both forms equally probable. Due to the high activation barrier (>40 kcal mol(-1)), a one-step, direct interconversion between the two forms turned out to be unfavourable. Moreover, the potential energy surface of fluvastatin was briefly inspected, revealing relatively small energetic differences (<5 kcal mol(-1)) between the key conformers.

X-ray diffraction and theoretical studies of the methyl ester of (R,R)-tartaric acid monoamide: semiempirical and ab initio calculations of some model compounds

Abstract In its crystal structure, determined by X-ray diffraction, the methyl ester of (R,R)-tartaric acid monoamide crystallizes with two molecules per assymetric unit. Each molecule displays subtle conformational differences effected by 180° rotation by the methyl ester group about the CC∗ bond, whereas the staggered conformation around the central C∗C∗ bond, with a trans arrangement of the ester and amide substituents, and the eclipsed orientation of the amide nitrogen atom with respect to the nearest hydroxyl group, remains the same in both molecules. MNDO and ab initio single-point energies for the two molecules indicate that the lower energy molecule is that with the α-hydroxyl group eclipsed by the carbonyl group rather than the methoxy oxygen atom. Conformers observed in the crystal structure differ from those obtained by full MNDO optimization in the planarity of α-hydroxyester and α-hydroxyamide residues. Ab initio calculations at the 6–31G∗ level on smaller systems, i.e. (2R,3R)-2,3-butanediol and (2R,3R)-2,3-dihydroxybutanedinitrile, suggest different conformational preferences for the two model compounds (gauche vs. trans with respect to the carbon chain), and point to the importance of the intramolecular hydrogen bond in stabilizing the gauche orientation of the vicinal OH groups. A similar hydrogen bond may be present in one of two crystallographically independent molecules of the methyl ester of (R,R)-tartaric acid monoamide, but only as a minor component in a complex system of intermolecular hydrogen bonds.

Palindromes in Proteins

Palindromes in DNA consist of nucleotides sequences that read the same from the 5′-end to the 3′-end, and its double helix is related by twofold axis. They occur in genomes of all organisms and have various functions. For example, restriction enzymes often recognize palindromic sequences of DNA. Palindromes in telomeres are crucial for initiation of replication. One can ask the questions, Do palindromes occur in protein, and if so, what function they play? We have searched the protein SWISSPROT database for palindromic sequences. A great number (26%) of different protein palindromes were found. One example of such protein is systemin, an 18-amino-acid-long peptide. It contains palindrome in its β-sheet domain that interacts with palindromic fragment of DNA. The other palindrome containing protein is cellular human tumor suppressor p53. Oligonucleotide LTIITL has been observed in the crystal structure and is located close to a DNA recognizing domain. As the number of possible palindromic sequences of a given length is far much greater for proteins (20N) than for nucleic acids (4N), the study on their role seems to be an exciting challenge. Our results have clearly showed that palindromes are frequently occurring motives in proteins. Moreover, even very few examples that we have examined so far indicate the importance of further studies on protein palindromes.

Unusual ion UO4 − formed upon collision induced dissociation of [UO2(NO3)3]−, [UO2(ClO4)3]−, [UO2(CH3COO)3]− ions

The following ions [UO2(NO3)3]−, [UO2(ClO4)3]−, [UO2(CH3COO)3]− were generated from respective salts (UO2(NO3)2, UO2(ClO4)3, UO2(CH3COO)2) by laser desorption/ionization (LDI). Collision induced dissociation of the ions has led, among others, to the formation of UO4− ion (m/z 302). The undertaken quantum mechanical calculations showed this ion is most likely to possess square planar geometry as suggested by MP2 results or strongly deformed geometry in between tetrahedral and square planar as indicated by DFT results. Interestingly, geometrical parameters and analysis of electron density suggest it is an UVI compound, in which oxygen atoms bear unpaired electron and negative charge.

The role of multiple parallel and antiparallel local dipoles for molecular structure and intermolecular interactions of oxalamides

The paper illustrates the role of dipole–dipole interactions in stabilizing the molecular structure and intermolecular interactions in oxalic acid diamides. A CSD search and quantum chemical calculations reveal that within the oxalamide molecule N–H and β(CO) bonds are oriented mutually parallel, so that the local dipoles formed along these bonds are antiparallel. Moreover, the all-trans conformation of secondary oxalamides gives rise to the cooperative intramolecular NH/CO and CH/CO dipolar interactions. Contrary to the situation in hydrogen bonded amide R22(8) dimers, in oxalamide R22(10) dimers the CO and N–H bonds from two different molecules are parallel, moreover, the angular distribution of proton donors around carbonyl acceptor is much more linear. These findings indicate the dominant role of dipole–dipole interactions in this bimolecular cyclic system. As parallel (and antiparallel) dipole–dipole interactions impose restraints on the position of four atoms such an approach provides an additional predictive value over the identification of hydrogen bonding that imposes restraints on the position of three atoms.

The MM2QM tool for combining docking, molecular dynamics, molecular mechanics, and quantum mechanics.

The use of the MM2QM tool in a combined docking + molecular dynamics (MD) + molecular mechanics (MM) + quantum mechanical (QM) binding affinity prediction study is presented, and the tool itself is discussed. The system of interest is Mycobacterium tuberculosis (MTB) pantothenate synthetase in complexes with three highly similar sulfonamide inhibitors, for which crystal structures are available. Starting from the structure of MTB pantothenate synthetase in the “open” conformation and following the combined docking + MD + MM + QM procedure, we were able to capture the closing of the enzyme binding pocket and to reproduce the position of the ligands with an average root mean square deviation of 1.6 Å. Protein–ligand interaction energies were reproduced with an average error lower than 10%. The discussion on the MD part and a protein flexibility importance is carried out. The presented approach may be useful especially for finding analog inhibitors or improving drug candidates.