Quantum-chemical study on the relative stability of sildenafil tautomers

The tautomeric equilibrium of sildenafil molecule was theoretically studied using B3LYP and M06-2X density functional theory (DFT) methods in connection with aug-cc-pVDZ correlation consistent basis set. Calculations were performed for gas phase and water solution conditions modelled by polarizable continuum model (PCM). Three tautomeric forms are possible. Two keto forms: A — where the tautomeric proton in more distant from carbonyl group and B — where it is closer, and one enol form denoted, C. Both DFT methods qualitatively give similar tautomer stability order: B > A > C. The B tautomer is dominant in gas phase and water environment, whereas the C tautomer is too high in energy to be present in the tautomeric mixture. Regarding the A tautomer, it is not present in the gas phase but is present in small amounts in water solution. According to B3LYP/aug-cc-pVDZ, the relative Gibbs-free energies for A and C relative to B are 10.05 kcal/mol and 11.91 kcal/mol for gas phase and 5.49 kcal/mol and 12.49 kcal/mol for water solution. According to M06-2X/aug-cc-pVDZ, the relative Gibbs-free energies for A and C are 9.12 kcal/mol and 10.60 kcal/mol for gas phase and 4.27 kcal/mol and 10.23 kcal/mol for water solution. Therefore, for in vivo conditions, we expect that the B tautomer is dominant, and there may exist small amounts of the A tautomer. The C enol tautomer is not present at all. This picture is very different from the parent tautomeric system: 4-hydroxypyrimidine/4-pyrimidinone where the C enol tautomer is less stable than keto B only by about 1 kcal/mol in the gas phase and the A keto tautomer is the least stable and not present in the tautomeric mixture. In order to understand these differences, we performed additional calculations for a series of parent molecules starting from 4-hydroxypyrimidine/4-pyrimidinone, going through two in-between model molecules and ending at Sildenafil molecule. We found that the most important reasons of C form destabilization are dearomatization of the 6-membered ring caused by the fusion with pyrazole ring, lack of strong intramolecular hydrogen bond in C form of sildenafil and presence of destabilizing steric interaction of oxygen and nitrogen atoms of two 6-memberd rings in this tautomer.

Quantum-Chemical Study on the Relative Stability of Sildenafil Tautomers

The tautomeric equilibrium of Sildenafil molecule was theoretically studied using B3LYP and M06-2X Density Functional Theory (DFT) methods in connection with aug-cc-pVDZ correlation consistent basis set. Calculations were performed for gas phase and water solution conditions modelled by Polarizable Continuum Model (PCM). Three tautomeric forms are possible. Two keto forms: A – where the tautomeric proton in more distant from carbonyl group, B – where it is closer, and one enol form denoted C. Both DFT methods qualitatively give similar tautomer stability order: B>A>C. The B tautomer is dominant in gas phase and water environment, whereas the C tautomer is too high in energy to be present in the tautomeric mixture. Regarding the A tautomer, it is not present in the gas phase but is present in small amounts in water solution. According to B3LYP/ aug-cc-pVDZ the relative Gibbs free energies for A and C relative to B, are 10.05 kcal/mol and 11.91 kcal/mol for gas phase and 5.49 kcal/mol and 12.49 kcal/mol for water solution. According to M06-2X/aug-cc-pVDZ the relative Gibbs free energies for A and C are 9.12 kcal/mol and 10.60 kcal/mol for gas phase and 4.27 kcal/mol and 10.23 kcal/mol for water solution. Therefore, for in vivo conditions we expect that the B tautomer is dominant and there may exist small amounts of the A tautomer. The C enol tautomer is not present at all. This picture is very different from the parent tautomeric system: 4-hydroxypyrimidine/4-pyrimidinone where the C enol tautomer is less stable than keto B only by about 1 kcal/mol in the gas phase and the A keto tautomer is the least stable and not present in the tautomeric mixture. In order to understand these differences we performed additional calculations for series of parent molecules starting from 4-hydroxypyrimidine/4-pyrimidinone, going through two in-between model molecules and ending at Sildenafil molecule. We found that the most important reasons of C form destabilization are: dearomatization of the 6-membered ring caused by the fusion with pyrazole ring, lack of strong intramolecular hydrogen bond in C form of Sildenafill and presence of destabilizing steric interaction of oxygen and nitrogen atoms of two 6-memberd rings in this tautomer.

In silico approach: docking study of oxindole derivatives against the main protease of COVID-19 and its comparison with existing therapeutic agents

Objectives Presently, the pandemic of COVID-19 has worsened the situation worldwide and received global attention. The United States of America have the highest numbers of a patient infected by this disease followed by Brazil, Russia, India and many other countries. Moreover, lots of research is going on to find out effective vaccines or medicine, but still, no potent vaccine or drug is discovered to cure COVID-19. As a consequence, many types of research have designated that computer-based studies, such as protein–ligand interactions, structural dynamics, and chembio modeling are the finest choice due to its low cost and time-saving features. Here, oxindole derivatives have been chosen for docking because of their immense pharmacological applications like antiviral, antidiabetic, anti-inflammatory, and so on. Molecular docking of 30 oxindole derivatives done on the crystallized structure of the protein (COVID-19 Mpro). Methods The process of docking, interaction, and binding the structure of ligand with protein has executed using Molegro Virtual Docker v.7.0.0 (MVD) and visualized the usage by Molegro Molecular Viewer v.7.0.0 (MMV). Results Among the 30 derivatives, the outcomes depicted better steric interaction and hydrogen bonding amongst OD-22 ligand, OD-16 ligand, OD-4 ligand, and OD-9 ligand (oxindole derivatives) with COVID-19. In addition to this, the comparative study of these four compounds with existing drugs that are under clinical trials shows comparatively good results in terms of its MolDock scores, H-bonding and steric interactions. Conclusions Hence, It is proposed that these four oxindole derivatives have good potential as a new drug against coronavirus as possible therapeutic agents.

On the Question of Steric Repulsion versus Noncovalent Attractive Interactions in Chiral Phosphoric Acid Catalyzed Asymmetric Reactions

The origin of enantioselectivity in asymmetric catalysis is often built around the differential steric interaction in the enantiocontrolling transition states (TSs). Closer perusal of enantiocontrolling TSs in an increasingly diverse...

In Silico Characterization and Prediction of Thiourea-like Neutral Bidentate Halogen Bond Catalysts

Preorganization is a common strategy to align halogen bond (XB) donors to form two or more halogen bonds simultaneously. Previous approaches have utilized various non-covalent interactions such as steric interaction,...

Crystal and molecular structures of dichloridopalladium(II) containing 2-methyl- or 2-phenyl-8-(diphenyphosphanyl)quinoline

The crystal structures of dichloridopalladium(II) complexes bearing 2-methyl- and 2-phenyl-8-(diphenylphosphanyl)quinoline, namely, dichlorido[8-(diphenylphosphanyl)-2-methylquinoline-κ2 N,P]palladium(II), [PdCl2(C22H18NP)] (1) and dichlorido[8-(diphenylphosphanyl)-2-phenylquinoline-κ2 N,P]palladium(II), [PdCl2(C27H20NP)] (2), were analyzed and compared to that of the 8-(diphenylphosphanyl)quinoline (PQH) analogue (3). In all three complexes, the phosphanylquinoline moiety acts as a bidentate P,N-donating chelate ligand. In the PQH complex (3), the PdII center has a typical planar coordination environment; however, both the methyl- and phenyl-substituted phosphanylquinoline (PQMe and PQPh, respectively) complexes (1) and (2) exhibit a considerable tetrahedral distortion around the PdII center, as parameterized by the τ4 values of 0.1555 (4) and 0.1438 (4) for (1) and (2), respectively. The steric interaction from the substituted group introduced at the 2-position of the quinoline ring enforces the cis-positioned Cl ligand to be displaced from the ideal coordination plane. Also, the ideally planar phosphanylquinoline five-membered chelate ring shows a large bending deformation by the displacement of the PdII center from the quinoline plane. In addition, in the phenyl-substituted complex (3), the coordinating quinolyl and the substituted phenyl rings are not co-planar to each other, having a dihedral angle of 33.08 (7)°. This twist conformation prohibits any intermolecular π–π stacking interaction between the quinoline planes, which is observed in the crystals of complexes (1) and (2).

Chitosan-Based Nanocomposites for Glyphosate Detection Using Surface Plasmon Resonance Sensor

This article describes an optical method based on the association of surface plasmon resonance (SPR) with chitosan (CS) film and its nanocomposites, including zinc oxide (ZnO) or graphene oxide (GO) for glyphosate detection. CS and CS/ZnO or CS/GO thin films were deposited on an Au chip using the spin coating technique. The characterization, morphology, and composition of these films were performed by Fourier-transform infrared spectroscopy (FTIR), atomic force microscopy (AFM), and contact angle technique. Sensor preparation conditions including the cross-linking and mobile phase (pH and salinity) were investigated and thoroughly optimized. Results showed that the CS/ZnO thin-film composite provides the highest sensitivity for glyphosate sensing with a low detection limit of 8 nM and with high reproducibility. From the Langmuir-type adsorption model and the effect of ionic strength, the adsorption mechanisms of glyphosate could be controlled by electrostatic and steric interaction with possible formation of 1:1 outer-sphere surface complexes. The selectivity of the optical method was investigated with respect to the sorption of glyphosate metabolite (aminomethylphosphonic acid) (AMPA), glufosinate, and one of the glufonisate metabolites (3-methyl-phosphinico-propionic acid) (MPPA). Results showed that the SPR sensor offers a very good selectivity for glyphosate, but the competition of other molecules could still occur in aqueous systems.

In Silico Study of 1,5-Bis(4-Hydroxy-3-Methoxyphenyl)-1,4-Pentadiene-3-One (Deketene Curcumin) on Crystallized Protein Structures of SARS-CoV-2

<p>World Health Organization (WHO) reveals total number of coronavirus cases are 5,684,802 and 352,225 deaths till today worldwide. Coronavirus instances are nevertheless surging due to its speedy spreading through infected patients. Therefore, in order to find potent vaccine almost every researcher is doing hard work to find it. However, until today there is not any availability of effective vaccine or drug for the treatment of COVID-19. In this case, the computational approach is the good choice to identify effective drugs and could be very useful due to its low cost, less error and less time consumption. Here, Deketene curcumin has taken for docking study because of its lots of biological applications such as antiviral, antimicrobial, anti-inflammatory, antioxidant, antibiotic, and to a name of few, it is a derivative of curcumin. In this study, five main protease crystallized COVID-19 structures (PDB ID: 6LU7, 5R7Z, 5R7Y, 5R80, 5R81) have been taken for simulation against deketene curcumin. Required procedure for this in silico study done through Molegro virtual docker (MVD) and Molegro Molecular Viewer (MMV) used for visualization. The results showed H-bonding and steric interaction between Deketene Curcumin with COVID-19 (PDB ID: 6LU7, 5R7Z, 5R7Y, 5R80, 5R81). Moldock scores of Deketene Curcumin Observed -134.198 kcal/mol, -151.972 kcal/mol, -109.224 kcal/mol, -140.741 kcal/mol and -126.562 kcal/mol with PDB Id 6LU7, 5R7Z, 5R7Y, 5R80 and 5R81 respectively. As per our results, it can be say that Deketene Curcumin has effective as a lead compound to find new antiviral drug candidates against COVID-19 for possible medicinal agent.</p>

In Silico Study of 1,5-Bis(4-Hydroxy-3-Methoxyphenyl)-1,4-Pentadiene-3-One (Deketene Curcumin) on Crystallized Protein Structures of SARS-CoV-2

<p>World Health Organization (WHO) reveals total number of coronavirus cases are 5,684,802 and 352,225 deaths till today worldwide. Coronavirus instances are nevertheless surging due to its speedy spreading through infected patients. Therefore, in order to find potent vaccine almost every researcher is doing hard work to find it. However, until today there is not any availability of effective vaccine or drug for the treatment of COVID-19. In this case, the computational approach is the good choice to identify effective drugs and could be very useful due to its low cost, less error and less time consumption. Here, Deketene curcumin has taken for docking study because of its lots of biological applications such as antiviral, antimicrobial, anti-inflammatory, antioxidant, antibiotic, and to a name of few, it is a derivative of curcumin. In this study, five main protease crystallized COVID-19 structures (PDB ID: 6LU7, 5R7Z, 5R7Y, 5R80, 5R81) have been taken for simulation against deketene curcumin. Required procedure for this in silico study done through Molegro virtual docker (MVD) and Molegro Molecular Viewer (MMV) used for visualization. The results showed H-bonding and steric interaction between Deketene Curcumin with COVID-19 (PDB ID: 6LU7, 5R7Z, 5R7Y, 5R80, 5R81). Moldock scores of Deketene Curcumin Observed -134.198 kcal/mol, -151.972 kcal/mol, -109.224 kcal/mol, -140.741 kcal/mol and -126.562 kcal/mol with PDB Id 6LU7, 5R7Z, 5R7Y, 5R80 and 5R81 respectively. As per our results, it can be say that Deketene Curcumin has effective as a lead compound to find new antiviral drug candidates against COVID-19 for possible medicinal agent.</p>