Positive Molecular Electrostatic Potential Research Articles

Scrutiny of Mitragynine and derivatives with analgesic potential using Mep and ligand-MOR interaction

Mitragynine and derivatives with analgesic activity were scrutinized to unravel key structural features necessary for biological activities and interactions with the m-opioid receptor (MOR). Molecular electrostatic potential (MEP) scrutiny showed the anionic and phenolic sites, as well as the hydrophobic region of opioids, important for analgesic activity, susceptible to electrophilic attack by a biological target and that the presence of bulky substituents at C9 and C7 can hinder analgesia, through steric hindrance, and increase the positive MEP region in the phenolic site. Scrutiny of the interaction with the MOR showed the most active opioids, in general, having the tertiary N atom of the anionic site closest to the C atom from the COOH of the Asp147 residue of the MOR. Furthermore, opioids present hydrogen bond interactions between the H atom from the OCH3 of the phenolic site with the phenolic O atom from the OH of the Tyr148 residue of the MOR and of the H atom from the OH of this residue with the O atom from the OCH3 of the hydrophobic region. The accumulated insights led to the design of new derivatives and the identification of two (2) of them as promising derivatives for synthesis and biological assays.

Small palladium clusters and their adducts with atomic oxygen

A systematic investigation on small Pdn clusters (n = 1 ÷ 8) and their interaction with atomic oxygen was conducted at DFT level. A model to describe cohesive energy for small sized clusters based on a topological approach was proposed and validated. On the basis of the bond length, the stabilisation electronic energy and the second electronic energy difference variation analysis, Pd4 and Pd6 were identified as the most stable clusters. The Natural Bond Orbital (NBO) analysis and the plot of the Molecular Electrostatic Potential (MEP) – both performed for the first time – indicated that the Pd atoms in clusters were not equivalent in terms of atomic charge, population and electron configuration. The plots of the MEP mapped on the electron density also revealed its non-uniform character; areas of positive MEP were found around the Pd atoms, which may undertake nucleophilic attacks. Subsequently, the interaction of atomic oxygen with Pdn clusters was systematically studied, accounting for different possible anchoring positions. The hollow site was revealed to be the most favourable one. The increase in number of Pd atoms favoured higher spin states. Pd6O was identified as the most oxidised and energetically stable cluster. The calculated binding energy value of oxygen (3.5 eV) was in agreement with the Temperature Programmed Desorption (TPD) experimental results conducted on Pd(1 1 0) single-crystal surface. The NBO analysis evidenced that the occupancy of 2 s (2p) orbital of O decreased (increased) as the number of Pd atom increased. The negatively charged Pd atoms had a larger population of 4d orbitals than the neutral or positively charged ones. The interactions between O and Pd atoms were dominated by d-type orbitals.

The chalcogen bond in F2P(S)N⋅⋅⋅SX2, F2PNS⋅⋅⋅SX2, F2PSN⋅⋅⋅SX2 (X = F, Cl, Br, OH, CH3, NH2) complexes.

As a kind of intermolecular noncovalent interaction, chalcogen bonding plays a critical role in the fields of chemistry and biology. In this paper, S⋅⋅⋅S chalcogen bonds in three groups of complexes, F2P(S)N⋅⋅⋅SX2, F2PNS⋅⋅⋅SX2, and F2PSN⋅⋅⋅SX2 (X = F, Cl, Br, OH, CH3, NH2), were investigated at the MP2/aug-cc-pVTZ level of theory. The calculated results show that the formation of S⋅⋅⋅S chalcogen bond is in the manner of attraction between the positive molecular electrostatic potential (VS,max) of chalcogen bond donator and the negative VS,min of chalcogen bond acceptor. It is found that a good correlation exists between the S⋅⋅⋅S bond length and the interaction energy. The energy decomposition indicates the electrostatic energy and polarization energy are closely correlated with the total interaction energy. NBO analysis reveals that the charge transfer is rather closely correlated with the polarization, and the charge transfer has a similar behavior as the polarization in the formation of complex. Our results provide a new example for interpreting the noncovalent interaction based on the σ-hole concept. Graphical abstract The chalcogen bonds in the studied binary complexes are Coulombic in nature, and the charge transfer has a similar behavior as the polarization in the formation of the complex.

Trifluoromethyl: An Amphiphilic Noncovalent Bonding Partner.

The traditional "Fδ- " picture of fluorine suggests that it can only interact with electrophilic centers such as backbone-carbonyl carbon atoms or hydrogen-bond donors in proteins. We show that this view, which neglects polarization, is incomplete and the trifluoromethyl groups can act both as electrophiles and nucleophiles to form noncovalent interactions. The underlying polarization mechanism is based on the anomeric effect and is only fully operative if the geometry is allowed to relax. MP2/aug-cc-pVDZ calculations on model systems demonstrate the effect of the unusual group polarizability of trifluoromethyl. A survey of the Protein Databank reveals more than 600 weak interactions involving a trifluorotoluene moiety. The unique combination of the anomeric effect and the group-polarization process associated with it in CF3 allows its most negative molecular electrostatic potential (MEP) on the surface in contact with a nucleophile to become zero, so that the area of positive MEP on the backside of the carbon atom becomes dominant. However, the reverse polarization is also facile, so that CF3 can also act as an H-bond acceptor for cations such as the guanidinium group of arginine.

A DFT study of substituent effects in corannulene dimers

Corannulene dimers made up of corannulene monomers with different curvature and substituents were studied using M06-2X, B97D and ωB97XD functionals and 6-31+G* basis set. Corannulene molecules were substituted with five alternating Br, Cl, CH(3), C(2)H or CN units. Geometric results showed that substituents gave rise to small changes in the curvature of corannulene bowls. So, there was not a clear relationship between the curvature of bowls and the changes on interaction energy generated by addition of substituents in the bowl. Electron withdrawing substituents gave rise to a more positive molecular electrostatic potential (MEP) of the bowl, which was able to get a strong interaction with the negative MEP at the surface of a fullerene. Substitution with CN caused the largest effect, giving rise to the most positive MEP and to a large interaction energy of -24.64 kcal mol(-1), at the ωB97XD/6-31+G* level. Dispersive effects must be taken into account to explain the catching ability of the different substituted corannulenes. For unsubstituted dimers, calculations with DFT-D methods employing ωB97XD and B97D functionals led to similar results to those previously reported at the SCS-MP2/cc-pVTZ level for corannulene dimers (A. Sygula and S. Saebø, Int. J. Quant. Chem., 2009, 109, 65). In particular, the ωB97XD functional led to a difference of only 0.35 kcal mol(-1), regarding MP2 interaction energy for corannulene dimers. On the other hand, the M06-2X functional showed a general considerable underestimation of interaction energies. This functional worked quite well to study trends, but not to obtain absolute interaction energies.

Intramolecular S···O chalcogen bond in thioindirubin

Results of X-ray diffraction study and quantum-chemical calculations revealed that molecular conformation of thioindirubin molecule creates suitable conditions for formation of intramolecular C–H···O and S···O interactions. Analysis of molecular electrostatic potential (MEP) demonstrates existence of two areas of positive MEP (σ-holes) in the outermost part of the sulfur atom on the continuation of the lines of the C–S bonds. One of these σ-holes is oriented toward region of negative MEP around the oxygen atom of carbonyl group. Such situation corresponds to formation of σ-hole or chalcogen bond. Existence of both types of bonding interactions is confirmed by topological analysis of electron density distribution using “Atoms in Molecules” (AIM) theory. Energies of the C–H···O hydrogen bond and the S···O σ-hole bond derived from AIM and NBO theories are very close.

AGOA hydration clusters produce the solvation effect on the aziridine···hydrofluoric acid complex — A modern proposal

The AGOA methodology was used to describe the hydration clusters of the C2H5N···HF heterocyclic hydrogen-bonded complex. Using the TIP4P water-geometry model, the hydration clusters were generated by analyzing the finite gradients of the molecular electrostatic potential (MEP) of the solute (C2H5N···HF). The results obtained revealed high hydration energies (ΔEHC-CORR) in the positive MEP field, indicating that the water molecules prefer to attack the methyl groups of the aziridine ring upon the formation of the C2H5N···HF hydrogen-bonded complex. Although they are in accordance with the experimental behavior of the aziridine acid-catalyzed open-ring reaction, the theoretical results obtained here provide a new perspective on studies of the solvation effect because the AGOA protocol requires little computational effort to create the hydration-cluster structures.

Structural analogues of reactive intermediates as inhibitors of glucosamine-6-phosphate synthase and phosphoglucose isomerase

The active centers of phosphoglucose isomerase (PGI) and the hexose phosphate isomerase domain (HPI) of glucosamine-6-P (GlcN-6-P) synthase demonstrate apparent similarity in spatial arrangement of critical amino acid residues, except Arg272 of the former and Lys603 and Lys485 of the latter. Ten derivatives of d-hexitol-6-P, 5-phosphoarabinoate, or 6-phosphogluconate, structural analogues of putative cis-enolamine or cis-enolate intermediates, were tested as inhibitors of fungal GlcN-6-P synthase and PGI. None of the investigated compounds demonstrated equally high inhibitory potential against both enzymes. 2-Amino-2-deoxy-D-mannitol 6-P was found to be the strongest GlcN-6-P synthase inhibitor in the series, with an inhibition constant equal to 9.0 (±1.0) × 10 −6 M. On the contrary, 5-phosphoarabinoate (5PA) exhibited specificity for PGI, with K i = 2.2 (±0.1) × 10 −6 M. N-acetylation substantially lowered the GlcN-6-P synthase inhibitory potential of 2-amino-2-deoxy- d-glucitol-6-P but strongly enhanced inhibitory potential of this compound towards PGI. Molecular modeling studies revealed that interactions of the C1–C2 part of transition state analogue inhibitors with the respective areas demonstrating different distribution of molecular electrostatic potential (MEP) inside HPI and PGI active centers determined enzyme:ligand affinity. In Escherichia coli HPI, a patch of the negative potential created by Glu488 aided by Val399, supposed to stabilize a putative positively charged intermediate, especially attracts ligands containing 2-amino function. The Arg272, Lys210, and Gly271 peptide bond nitrogen system, present in the corresponding space of rabbit PGI, creates an area of positive MEP, stabilizing cis-enolate intermediate and attracting its structural mimics, such as 5PA.

Molecular basis of the low activity of antitumor anthracenediones, mitoxantrone and ametantrone, in oxygen radical generation catalyzed by NADH dehydrogenase. Enzymatic and molecular modelling studies

Synthetic antitumor anthracenedione drugs, in contrast to anthracycline antibiotics, are ineffective in free radical formation in NADH dehydrogenase system. Our results have indicated that neither the reduction potential nor the side chain conformation and the energies of border orbitals (HOMO and LUMO) determine the ability of anthracenediones to stimulate reactive oxygen species formation in NADH dehydrogenase system. It was shown that the distribution of the molecular electrostatic potential (MEP), around the quinone system was crucial for this ability. We have found for non-stimulating anthracenediones that the clouds of positive MEP cover the quinone carbon atoms while for agents effective in stimulating reactive oxygen species formation the clouds of negative MEP cover continuously the aromatic core together with the quinone system.

Molecular modelling investigation of wild-type and the R528H mutated segment IIS4 of human L-type voltage-gated calcium channels.

A molecular modelling study was performed in order to investigate the pathologically modified properties of L-type voltage-gated calcium channels caused by the arginine-to-histidine mutation at position 528 (R528H) in segment IIS4. For an appropriate consideration of the ionization state the finite difference Poisson-Boltzmann method was applied to compute the apparent pKa values of all titratable residues using standard conditions and an explicit lipophilic environment, respectively. Restrained molecular dynamics simulations were carried out for the alpha-helical transmembrane segments of the wild-type and the R528H mutant to explore their conformational behaviour. While both structures showed almost the same side-chain flexibility around the conserved residues, only the mutant partially formed a hydrogen bond from H528 to R531 during dynamics simulations. This local interaction not only causes a lower mobility of the directly involved residues but also leads to a global distortion of all positively charged amino acids of the mutant. Mostly affected is the side-chain of R534 that is shifted about 61 degrees closer to R531 and about 5 A in the direction of the cytoplasm. Subsequent examination of the molecular characteristics of this putative voltage sensor of the channel revealed considerable variations with regard to hydrogen bonding and electronic properties. Most obvious are the dramatic loss of a strong positive molecular electrostatic potential and the reduced hydrogen donor activities around position 528 of the mutant. How these results may be interpreted in relation to an enhanced inactivation rate is discussed, considering earlier findings at homologous voltage-gated potassium and sodium channels.

3‐D QSAR for intrinsic activity of 5‐HT1A receptor ligands by the method of comparative molecular field analysis

AbstractThe affinity of a ligand for a receptor is usually expressed in terms of the dissociation constant (Ki) of the drug‐receptor complex, conveniently measured by the inhibition of radioligand binding. However, a ligand can be an antagonist, a partial agonist, or a full agonist, a property largely independent of its receptor affinity. This property can be quantitated as intrinsic activity (1A), which can range from 0 for a full antagonist to 1 for a full agonist. Although quantitative structure–activity relationship (QSAR) methods have been applied to the prediction of receptor affinity with considerable success, the prediction of IA, even qualitatively, has rarely been attempted. Because most traditional QSAR methods are limited to congeneric series, and there are often major structural differences between agonists and antagonists, this lack of success in predicting IA is understandable. To overcome this limitation, we used the method of comparative molecular field analysis (CoMFA), which, unlike traditional Hansch analysis, permits the inclusion of structurally dissimilar compounds in a single QSAR model. A structurally diverse set of 5‐hydroxytryptamine1A (5‐HT1A) receptor ligands, with literature IA data (determined by the inhibition of 5‐HT sensitive forskolin‐stimulated adenylate cyclase), was used to develop a 3‐D QSAR model correlating intrinsic activity with molecular structure properties of 5HT1A receptor ligands. This CoMFA model had a crossvalidated r2 of 0.481, five components and final conventional r2 of 0.943. The receptor model suggests that agonist and antagonist ligands can share parts of a common binding site on the receptor, with a primary agonist binding region that is also occupied by antagonists and a secondary binding site accommodating the excess bulk present in the sidechains of many antagonists and partial agonists. The CoMFA steric field graph clearly shows that agonists tend to be “flatter” (more coplanar) than antagonists, consistent with the difference between the 5‐HT1A agonist and antagonist pharmacophores proposed by Hibert and coworkers. The CoMFA electrostatic field graph suggests that, in the region surrounding the essential protonated aliphatic amino group, the positive molecular electrostatic potential may be weaker in antagonists as compared to agonists. Together, the steric and electrostatic maps suggest that in the secondary binding site region increased hydrophobic binding may enhance antagonist activity. These results demonstrate that CoMFA is capable of generating a statistically crossvalidated 3‐D QSAR model that can successfully distinguish between agonist and antagonist 5‐HT1A ligands. To the best of our knowledge, this is the first time this or any other QSAR method has been successfully applied to the correlation of structure with IA rather than potency or affinity. The analysis has suggested various structural features associated with agonist and antagonist behaviors of 5‐HT1A ligands and thus should assist in the future design of drugs that act via 5‐HT1A receptors. © 1993 John Wiley & Sons, Inc.