Presence Of Hydrogen Bond Acceptors Research Articles

4,4′-Azobis(1,2,4-triazole): A Versatile Molecular Scaffold to Develop Tailor-Made Energetic Materials

Energetic materials containing azoles are appealing in terms of their high nitrogen content and presence of functional groups that can participate in different non-covalent bonding interactions. One such interesting compound is 4,4′-azobis(1,2,4-triazole) (ATRZ), which has formidable energetic parameters. Based on the presence of hydrogen-bond acceptor and metal coordination sites, a number of tailor-made energetic materials have been derived by employing ATRZ as the molecular precursor. In this review, we discuss the use of this high-energy molecular scaffold in the development of different energetic cocrystals, coordination polymers, and composites and discuss their properties in the context of state-of-the-art energetic materials.

Traditional herbal compounds as candidates to inhibit the SARS-CoV-2 main protease: an in silico study

COVID-19, a disease caused by the SARS-CoV-2 virus, is responsible for a pandemic since March 2020 and it has no cure. Therefore, herein, different theoretical methods were used to obtain potential candidates from herbal compounds to inhibit the SARS-CoV-2 main protease (Mpro). Initially, the 16 best-scored compounds were selected from a library containing 4066 ligands using virtual screening by molecular docking. Among them, six molecules (physalin B 5,6-epoxide (PHY), methyl amentoflavone (MAM), withaphysalin C (WPC), daphnoline or trilobamine (TRI), cepharanoline (CEP) and tetrandrine (TET)) were selected based on Lipinski’s rule and ADMET analysis as criteria. These compounds complexed with the Mpro were submitted to triplicate 100 ns molecular dynamics simulations. RMSD, RMSF, and radius of gyration results show that the overall protein structure is preserved along the simulation time. The average ΔGbinding values, calculated by the MM/PBSA method, were −41.7, −55.8, −45.2, −38.7, −49.3, and −57.9 kcal/mol for the PHY-Mpro, MAM-Mpro, WPC-Mpro, CEP-Mpro, TRI-Mpro, and TET-Mpro complexes, respectively. Pairwise decomposition analyses revealed that the binding pocket is formed by His41-Val42, Met165-Glu166-Leu167, Asp187, and Gln189. The PLS regression model generated by QSPR analysis indicated that non-polar and polar groups with the presence of hydrogen bond acceptors play an important role in the herbal compounds-Mpro interactions. Overall, we found six potential candidates to inhibit the SARS-CoV-2 Mpro and highlighted key residues from the binding pocket that can be used for future drug design. Communicated by Ramaswamy H. Sarma

Diphenanthrioctaphyrin(1.1.1.0.1.1.1.0): Conformational Switching Controls the Stereochemical Dynamics of the Topologically Chiral System.

The analogue of octaphyrin(1.1.1.0.1.1.1.0) bearing two dimethoxyphenanthrene units was synthesized and characterized in solution and solid state. The macrocycle was demonstrated to exist as two locked conformers that can be easily separated and handled individually. The conversion of conformers was proven to be facilitated by the presence of hydrogen-bond acceptors, such as amines. The bis-boron(III) complex of diphenanthrioctaphyrin has been obtained, proving that the metalloid center acts as the topology selector stabilizing only one conformation of the macrocycle, irrespective of the stereoisomer used for the insertion. Both conformers of diphenanthrioctaphyrin, as well as the boron complex formed from them, have been separated into enantiomers using HPLC with a chiral stationary phase. All of these systems have shown strikingly different stereodynamic behavior.

3D-QSAR and docking studies of the stability constants of different guest molecules with beta-cyclodextrin

This study aims at developing a three dimensional quantitative structure–activity relationship (3D-QSAR) model for predicting complexation of a variety of 126 organic compounds with β-cyclodextrins (β-CD). Molecular descriptors were computed using GRid INdependent Descriptors (GRIND) approach. After variable selection via genetic algorithm method, GRIND are correlated with β-CD complexes stability constants by PLS regression. Kennard–Stone algorithm selected a training dataset comprised of 98 guest molecules. This strategy led to a final QSAR model that showed good internal cross-validation statistics and good predictivity on external data. Those GRIND information which influencing the complexation with β-CD were also confirmed by the 3D-QSAR and docking studies. All these information revealed that the presence of hydrogen bond acceptor and hydrogen bond donor groups in the molecules caused a more difficult and/or unfavorable complexation reaction with β-CDs. The size and shape of the molecules as well as hydrogen bonding interactions effects on the stabilities of β-CDs in inclusion complexes are discussed.

Molecular Mapping and Docking Interactions for Selective Anti-Fertility Potency of Estrogen Analogs

Estrogen, the key regulator of the cellular process involved in the development and maintenance of reproductive functions, mediates its action through estrogen receptor binding, and initiating a series of cellular pathway producing estrogen-induced responses. At higher dose, it can effectively act as contraceptive but associates with risk factors. Considering the long-term benefit-to-risk ratio of estrogen analogs as oral contraceptives, the present in-silico study has been focussed to deduce the active pharmacophore features required to differentiate the anti-fertility potency from estrogenic activity of steroidal motif. Hydrophobicity is an essential property for promoting both the functionalities, but molecular conformation and presence of hydrogen bond acceptors have been deduced to be the distinguishing features of anti-fertility activity of estrogen analogs as revealed from the molecular field and similarity analyses, and receptordependent docking studies. Keywords: Estrogen analogs, Estrogenic potency, Anti-fertility potency, Molecular field and similarity analyses, Ligand-receptor interaction, Virtual screening, cellular process, Molecular Mapping, docking, pharmacophore, molecular field, thromboembolic diseases, cancer, 3D QSAR methods, CoMFA

Modeling of diarylalkyl‐imidazole and diarylalkyl‐triazole derivatives as potent aromatase inhibitors for treatment of hormone‐dependent cancer

Aromatase is an enzyme that catalyzes the final step in the conversion of androgen to estrogen. It has become an attractive target for the treatment of estrogen responsive breast cancer. The study has been focused on designing aromatase inhibitors (AIs) that can be selected as probable drug candidate for the treatment of breast cancer. In the present study, long chain diarylalkyl-imidazole and -triazole scaffolds have been considered for exploring pharmacophores as potent AIs using QSAR (Quantitative SAR) and pharmacophore mapping studies. The model generated in linear free energy QSAR study (R(2) = 0.905, Q(2)= 0.885, R(2)(pred(ts)) = 0.763) showed the importance of hydrophobicity, size and shape of the molecule, van der Waals surface and hydrogen atom contribution influence the activity. 3D QSAR of comparative molecular field analysis (CoMFA, R(2)= 0.921, Q(2) = 0.741, R(2)(pred(ts))= 0.583) showed that steric and electrostatic features along with hydrophobicity and electronic charge contribution at C(4) (Fig. 1) influence on the inhibitory activity. Comparative molecular similarity analysis (CoMSIA, R(2) = 0.874, Q(2) = 0.716, R(2)(pred(ts)) = 0.591) study adjudged the presence of steric, electrostatic and hydrophobic fields together with hydrogen bond (HB) donor and acceptor play significant role in inhibitory activity to aromatase enzyme. Further pharmacophore mapping study (Q(2) = 0.947, Delta(cost) = 113.171, R(2)(pred(ts)) = 0.857) suggested that presence of HB acceptor, hydrophobicity with aromatic ring, and the importance of steric contribution influence on the activity. The critical distances among the features are also important for the inhibitor activity.

Interaction of Organic Cations with Organic Anion Transporters

Studies of the organic anion transporters (Oats) have focused mainly on their interactions with organic anionic substrates. However, as suggested when Oat1 was originally identified as NKT (Lopez-Nieto, C. E., You, G., Bush, K. T., Barros, E. J., Beier, D. R., and Nigam, S. K. (1997) J. Biol. Chem. 272, 6471-6478), since the Oats share close homology with organic cation transporters (Octs), it is possible that Oats interact with cations as well. We now show that mouse Oat1 (mOat1) and mOat3 and, to a lesser degree, mOat6 bind a number of "prototypical" Oct substrates, including 1-methyl-4-phenylpyridinium. In addition to oocyte expression assays, we have tested binding of organic cations to Oat1 and Oat3 in ex vivo assays by analyzing interactions in kidney organ cultures deficient in Oat1 and Oat3. We also demonstrate that mOat3 transports organic cations such as 1-methyl-4-phenylpyridinium and cimetidine. A pharmacophore based on the binding affinities of the tested organic cations for Oat3 was generated. Using this pharmacophore, we screened a chemical library and were able to identify novel cationic compounds that bound to Oat1 and Oat3. These compounds bound Oat3 with an affinity higher than the highest affinity compounds in the original set of prototypical Oct substrates. Thus, whereas Oat1, Oat3, and Oat6 appear to function largely in organic anion transport, they also bind and transport some organic cations. These findings could be of clinical significance, since drugs and metabolites that under normal physiological conditions do not bind to the Oats may undergo changes in charge and become Oat substrates during pathologic conditions wherein significant variations in body fluid pH occur.

Polarization of Water in the First Hydration Shell of K+ and Ca2+ Ions

Accurate representation of the interactions of water molecules with charges is essential for correct description of biomolecules and their interactions and, hence, is a primary concern in the design of classical force fields. This task is made even more challenging by the fact that the charge distribution of water molecules in liquid is significantly altered by the local environment. To understand how such polarization effects would modify the force fields, we have performed density functional calculations for ion-water clusters using K+ and Ca2+ ions as probes. We find that the dipole moment of water molecules in the first hydration shell decreases with increasing number of waters, which is explained by the suppression of the ion's electric field by those of water dipoles. Adding further water beyond the first shell, the dipole moment of the first shell waters increases because water dipoles are strongly polarized in the presence of hydrogen bond acceptors. Thus the net polarization of water in the hydration shell of an ion is determined by two competing effects, of which only one directly depends on the ion. These observations explain why the dipole moment of waters in the first hydration shell of a K+ ion is smaller compared to those in bulk water while the opposite is true for Ca2+ ions and suggest new constraints to be used in the development of polarizable water models.

Pharmacophore mapping of flavone derivatives for aromatase inhibition

Aromatase, which catalyses the final step in the steroidogenesis pathway of estrogen, has been target for the design of inhibitor in the treatment of hormone dependent breast cancer for postmenopausal women. The extensive SAR studies performed in the last 30 years to search for potent, selective and less toxic compounds, have led to the development of second and third generation of non-steroidal aromatase inhibitors (AI). Besides the development of synthetic compounds, several naturally occurring and synthetic flavonoids, which are ubiquitous natural phenolic compounds and mediate the host of biological activities, are found to demonstrate inhibitory effects on aromatase. The present study explores the pharmacophores, i.e., the structural requirements of flavones (Fig. 1) for inhibition of aromatase activity, using quantitative structure activity relationship (QSAR) and space modeling approaches. The classical QSAR studies generate the model (R (2) = 0.924, Q (2) = 0.895, s = 0.233) that shows the importance of aromatic rings A and C, along with substitutional requirements in meta and para positions of ring C for the activity. 3D QSAR of Comparative Molecular Field Analysis (CoMFA, R (2) = 0.996, R(2)(cv) = 0.791) and Comparative Molecular Similarity Analysis (CoMSIA, R (2) = 0.992, R(2)(cv) = 0.806) studies show contour maps of steric and hydrophobic properties and contribution of acceptor and donor of the molecule, suggesting the presence of steric hindrance due to ring C and R''-substituent, bulky hydrophobic substitution in ring A, along with acceptors at positions 11, and alpha and gamma of imidazole ring, and donor in ring C favor the inhibitory activity. Further space modeling (CATALYST) study (R = 0.941, Delta( cost ) = 96.96, rmsd = 0.876) adjudge the presence of hydrogen bond acceptor (keto functional group), hydrophobic (ring A) and aromatic rings (steric hindrance) along with critical distance among features are important for the inhibitory activity.

Fluorescent properties of hydrogen-bonded ellipticine: A special effect of fluoride anion

Fluorescence properties of ellipticine, a plant alkaloid, was studied in the presence of hydrogen-bond acceptors, such as F −, CH 3COO −, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and N-methylimidazole in different solvents. Global analysis of the spectrophotometric titration data proved that ellipticine deprotonation in the ground state occurred only in the case of the interaction with two F − anions in acetonitrile. The fluorescence band of the 1:1 complex of anions showed large Stokes shift implying significant proton displacement upon excitation along the hydrogen-bond. The lack of ellipticine-DBU complex emission was rationalized by quick proton transfer in the excited state. The kinetics and mechanism of the excited ellipticine quenching were also revealed.

X‐ray reflectivity study of cyclic peptide monolayers at the air‐water interface

AbstractThe dynamic and living characteristics of monolayers at the air‐water interface of a cyclohexapeptide (C6G) and a cyclooctapeptide (C8G), both composed of glutamic acid and 3‐aminobenzoic acid subunits in an alternating sequence, were investigated using the Langmuir balance technique, Brewster angle microscopy (BAM), and X‐ray reflectivity (XR). An alanine‐containing cyclohexapeptide (C6A) was included in this study for comparison. All three cyclopeptides preferentially adopt an orientation parallel to the subphase at low surface pressure. Continuous compression then causes the molecules to flip to a perpendicular state, thus minimizing their molecular area. In contrast to C8G and C6A, a pronounced hysteresis observed during the compression‐expansion cycle of C6G indicates that strong intermolecular interactions between the cyclopeptide rings occur in the monolayers of this peptide. This result is supported by BAM measurements that show the formation of crystallite structures for C6G at high surface pressures, whereas no structures were observed for C8G and C6A. These results indicate that C6G is able to self‐assemble upon surface compression, an ability that is obviously critically dependent on the correct ring size and composition of the peptide. The presence of hydrogen bond acceptors in the side chains of C6G suggests that the structural stabilization of the monolayer is due to H‐bonding, possibly between ring NH groups and side chain CO groups. Our in situ study thus provides a detailed understanding of the molecular dynamics and uninterrupted interfacial behavior of the three peptides in a real‐time frame.