New Insight into the Pharmacological Importance of Atropine as the Potential Inhibitor of AKR1B1 via Detailed Computational Investigations: DFTs, ADMET, Molecular Docking, and Molecular Dynamics Studies.

The aim of this research is to investigate the quantum geometric properties and chemical reactivity of atropine, a pharmaceutically active tropane alkaloid. Using density functional theory (DFT) computations with the B3LYP/SVP functional theory basis set, the most stable geometry of atropine was determined. Additionally, a variety of energetic molecular parameters were calculated, such as the optimized energy, atomic charges, dipole moment, frontier molecular orbital energies, HOMO-LUMO energy gap, molecular electrostatic potential, chemical reactivity descriptors, and molecular polarizability. To determine atropine's inhibitory potential, molecular docking was used to analyze ligand interactions within the active pockets of aldo-keto reductase (AKR1B1 and AKR1B10). The results of these studies showed that atropine has greater inhibitory action against AKR1B1 than AKR1B10, which was further validated through molecular dynamic simulations by analyzing root mean square deviation (RMSD) and root mean square fluctuations (RMSF). The results of the molecular docking simulation were supplemented with simulation data, and the ADMET characteristics were also determined to predict the drug likeness of a potential compound. In conclusion, the research suggests that atropine has potential as an inhibitor of AKR1B1 and could be used as a parent compound for the synthesis of more potent leads for the treatment of colon cancer associated with the sudden expression of AKR1B1.

New Organic-Inorganic Salt Based on Fluconazole Drug: TD-DFT Benchmark and Computational Insights into Halogen Substitution.

In this study, we report the synthesis of a new organic-inorganic molecular salt of the clinically used antifungal drug fluconazole, (H2Fluconazole).SnCl6.2H2O. By detailed investigation and analysis of its structural properties, we show that the structure represents a 0D structure built of alternating organic and inorganic zig-zag layers along the crystallographic c-axis and the primary supramolecular synthons in this salt are hydrogen bonding, F···π and halogen bonding interactions. Magnetic measurements reveal the co-existence of weak ferromagnetic behavior at low magnetic field and large diamagnetic contributions, indicating that the synthesized material behaves mainly as a diamagnetic material, with very low magnetic susceptibility and with a band gap energy of 3.6 eV, and the salt is suitable for semiconducting applications. Extensive theoretical study is performed to explain the acceptor donor reactivity of this compound and to predict the Cl-substitution effect by F, Br and I. The energy gap, frontier molecular orbitals (FMOs) and the different chemical reactivity descriptors were evaluated at a high theoretical level. Calculations show that Cl substitution by Br and I generates compounds with more important antioxidant ability and the intramolecular charge transfer linked to the inorganic anion.

Quantum mechanics and 3D-QSAR studies on thienopyridine analogues: inhibitors of IKKß.

Inhibitor of kappa B kinase subunit ß (IKKß) is a main regulator of nuclear factor kappa B (NF-κB) and has received considerable attention as an attractive therapeutic target for the treatment of lung cancer or other inflammatory disease. A group of diversified thienopyridine derivatives exhibited a wide range of biological activity was used to investigate its structural requirements by using DFT and 3D-Quantitative structure activity relationship. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were established using the experimental activity of thienopyridine derivatives. The cross-validation coefficient (q2) values for CoMFA and CoMSIA are 0.671 and 0.647 respectively, were achieved, demonstrating high predictive capability of the model. The contour analysis indicate that presence of hydrophobic and electrostatic field is highly desirable for biological activity. The results indicate that substitution of hydrophobic group with electron withdrawing effect at R4 and R6 position have more possibility to increase the biological activity of thienopyridine derivatives. Subsequently molecular docking and DFT calculation were performed to assess the potency of the compounds.

Chemical reactivity and adsorption properties of pro-carbazine anti-cancer drug on gallium-doped nanotubes: a quantum chemical study.

In this study, we propose new armchair single-walled nanotubes (SWNTs) for stable adsorption, increasing drug delivery performance and decreasing side effects of pro-carbazine (Pro-CB) anti-cancer in the framework of B3LYP/6-31 g*/Lanl2DZ level of theory. Indeed, doping gallium (Ga) metal in SWNTs is naturally followed by changing of geometry, increasing dipole moment, and creating one site with high reactivity in order to better adsorption of the drug molecule. Chemical reactivity descriptors show that SWNTs and Pro-CB have electrophile and nucleophile roles in interaction, respectively. More importantly, high local and dual softness in Ga-doped SWNTs indicate improvement of drug adsorption. Parallel and perpendicular complexes result from their interaction in the N and the O sites. Negative values of binding energy (Ebind) show that composed complexes are energetically stable especially in the O site in comparison with the N site. On the other hand, more negative value of the Ebind in SWCNTs shows that these nanotubes are more effective for drug adsorption than their boron nitride counterparts. Graphical abstract The Ga dopping results in reducing of HOMO-LUMO gap and increasing charge transfer between SWNTs and Pro-CB, and formation better complex, especially SWCNT.

Analyzing the substitution effect on the CoMFA results within the framework of density functional theory (DFT).

Though QSAR was originally developed in the context of physical organic chemistry, it has been applied very extensively to chemicals (drugs) which act on biological systems, in this idea one of the most important QSAR methods is the 3D QSAR model. However, due to the complexity of understanding the results it is necessary to postulate new methodologies to highlight their physical-chemical meaning. In this sense, this work postulates new insights to understand the CoMFA results using molecular quantum similarity and chemical reactivity descriptors within the framework of density functional theory. To obtain these insights a simple theoretical scheme involving quantum similarity (overlap, coulomb operators, their euclidean distances) and chemical reactivity descriptors such as chemical potential (µ), hardness (ɳ), softness (S), electrophilicity (ω), and the Fukui functions, was used to understand the substitution effect. In this sense, this methodology can be applied to analyze the biological activity and the stabilization process in the non-covalent interactions on a particular molecular set taking a reference compound.

Exploring the biological promiscuity of high-throughput screening hits through DFT calculations.

The goal of this study is the understanding of biologically promiscuous compounds (frequent hitters) in HTS outcomes through their chemical behavior estimated via reactivity descriptors. Chemical reactivity is often an undesirable property due to the lack in biological selectivity of compounds comprised in HTS libraries. In this study the reactivity indexes have been computed within the DFT formalism, at different levels of theory, for two classes of representative compounds compiled from PubChem database, one comprising frequent hitters and the second one comprising rare hitters (biologically more selective compounds). We found that frequent hitters exert increased reactivity, mainly due to their electrophilic character, compared to the more selective class of compounds.