Computational Study of Hydrogen Bonding in CH3CN•••H-X (X=OH, F, Cl, NH2) Complexes

In this work, first principles study of acetonitrile complexes (acetonitrile•••H-X, X=F, Cl, NH2, OH) has been carried out using electrostatic potential analysis, ab initio (MP2/6-311++g(2d, 2p), B3LYP/6-311++g(2d, 2p) and AIM theoretical calculations and these calculations confirm the hydrogen bonding interaction for these complexes. The geometrical parameters, binding energy and (3, -1) bond critical points confirm that HF donor is found to form strong hydrogen bond and NH3 donor is found to form weaker hydrogen bond for these complexes.

Crystal structure of osimertinib mesylate Form B (Tagrisso), (C28H34N7O2)(CH3O3S)

The crystal structure of osimertinib mesylate Form B has been solved and refined using synchrotron X-ray powder diffraction data and optimized using density functional techniques. Osimertinib mesylate Form B crystallizes in space group P-1 (#2) with a = 11.42912(17), b = 11.72274(24), c = 13.32213(22) Å, α = 69.0265(5), β = 74.5914(4), γ = 66.4007(4)°, V = 1511.557(12) Å3, and Z = 2. The crystal structure is characterized by alternating layers of cation–anion and parallel stacking interactions parallel to the ab-planes. The cation is protonated at the nitrogen atom of the dimethylamino group, which forms a strong hydrogen bond between the cation and the anion. That hydrogen atom also participates in a weaker intramolecular hydrogen bond to an amino nitrogen. There are two additional N–H⋅⋅⋅O hydrogen bonds between the cation and the anion. Several C–H⋅⋅⋅O hydrogen bonds also link the cations and anions. The powder pattern has been submitted to ICDD® for inclusion in the Powder Diffraction File™.

Self-Healing Hydrogels Based on Sodium Carboxymethyl Cellulose/Poly(vinyl alcohol) Reinforced with Montmorillonite

Currently, self-healing hydrogels prepared from the green process have been studied for various applications, especially in the biomedical field. This work fabricated the self-healing hydrogel based on sodium carboxymethyl cellulose/poly(vinyl alcohol)/montmorillonite by acidifying the mixture with citric acid. SEM measurements showed well-dispersed montmorillonite in the hydrogels. Cytotoxicity values >100% were seen with montmorillonite added, which indicated cell growth and no cell toxicity. Montmorillonite addition not only reinforced the networks but also improved self-healing ability. The tensile strength of the original uncut hydrogel with montmorillonite (P1C8M1) was 61 kPa, whereas the healed hydrogel showed 57 kPa. The hydrogel healed completely within 10 days, without any cracks, i.e., a 93% healing efficiency, or higher than the ~60% of the non-reinforced hydrogel. This confirmed strong hydrogen bond formation between the polymer and montmorillonite. The self-healing ability of this non-toxic hydrogel, reinforced with montmorillonite, makes it valuable for use in biomedical fields.

Crystal structures of two alanylpiperidine analogues

The structure of ethyl 1-[N-(4-methylphenyl)-N-(methylsulfonyl)alanyl]piperidine-4-carboxylate, C19H28N2O5S, I, a compound of interest as activator of Ubiquitin C-terminal Hydrolase-L1 (UCH-L1), was determined by single-crystal X-ray diffraction (SCXRD) analysis. In order to find new activators, a derivative of compound I, namely, 1-[N-(4-methylphenyl)-N-(methylsulfonyl)alanyl]piperidine-4-carboxylic acid, C17H24N2O5S, II, was studied. The synthesis and crystal structure are also reported. Despite being analogues, different crystal packings are observed. Compound II bears a carboxylic group, which favors a strong hydrogen bond. A polymorph risk assessment was carried out to study interactions in compound II.

Functional and structural analysis of catabolite control protein C that responds to citrate

Catabolite control protein C (CcpC) belongs to the LysR-type transcriptional regulator (LTTR) family, which regulates the transcription of genes encoding the tricarboxylic acid branch enzymes of the TCA cycle by responding to a pathway-specific metabolite, citrate. The biological function of CcpC has been characterized several times, but the structural basis for the molecular function of CcpC remains elusive. Here, we report the characterization of a full-length CcpC from Bacillus amyloliquefaciens (BaCcpC-FL) and a crystal structure of the C-terminal inducer-binding domain (IBD) complexed with citrate. BaCcpC required both dyad symmetric regions I and II to recognize the citB promoter, and the presence of citrate reduced citB promoter binding. The crystal structure of CcpC-IBD shows two subdomains, IBD-I and IBD-II, and a citrate molecule buried between them. Ile100, two arginines (Arg147 and Arg260), and three serines (Ser129, Ser189, and Ser191) exhibit strong hydrogen-bond interactions with citrate molecules. A structural comparison of BaCcpC-IBD with its homologues showed that they share the same tail-to-tail dimer alignment, but the dimeric interface and the rotation between these molecules exhibit significant differences. Taken together, our results provide a framework for understanding the mechanism underlying the functional divergence of the CcpC protein.

Designing of some Novel Methyl 2-((4-(Benzamido)Phenyl)Sulfanyl)-1,2,3,4-tetrahydro-6-Methylpyrimidine-5-carboxylate Derivatives as Potential Glucokinase Activators through Molecular Docking

Aims: Glucokinase (GK) is a cytoplasmic enzyme that metabolizes the glucose to glucose- 6-phosphate and supports the adjusting of blood glucose levels within the normal range in humans. In pancreatic β-cells, it plays a leading role by governing the glucose-stimulated secretion of insulin and in liver hepatocyte cells, it controls the metabolism of carbohydrates. GK acts as a promising drug target for the treatment of patients with type 2 diabetes mellitus (T2DM). Study Design: In the current study, the goal is to identify new substituted benzamide derivatives and test them via molecular docking as possible anti-diabetic drugs. Place and Duration of Study: The present work has been carried out at S.N.J.B’s S.S.D.J. College of Pharmacy, Neminagar, Chandwad, Nashik, Maharashtra, India during the time period of December-2020 to February-2021. Methodology: This work involved designing novel methyl 2-((4-(benzamido)phenyl)sulfanyl)-1,2,3,4-tetrahydro-6-methylpyrimidine-5-carboxylate derivatives and their screening by molecular docking studies to determine the binding interactions for the best-fit conformations in the binding site of the GK enzyme. Autodockvina 1.1.2 in PyRx 0.8 was used to perform the docking studies of all the designed novel derivatives and native ligand against the crystal structure of GK. Based on the results of docking studies, the selected molecules will be tested for their antidiabetic activity in the animal models. Results: Amongst the designed derivatives, compounds A2, A3, A8, A10, A11, A13, A14, A16, A17, and A18 have shown better binding free energy (between -8.7 to -10.3 kcal/mol) than the native ligand present in the enzyme structure. In present investigation, many molecules had formed strong hydrogen bond with Arg-63 which indicate the potential to activate GK. Conclusion: From above results it has been observed that these designed benzamide derivatives have potential to activate the human GK which enables us to proceed for the syntheses of these derivatives.

Simulation, In Vitro, and In Vivo Cytotoxicity Assessments of Methotrexate-loaded pH-Responsive Nanocarriers

In this study, pH-responsive niosomal methotrexate (MTX) modified with ergosterol was prepared for potential anticancer application. The prepared formulation had a size of 176.7 ± 3.4 nm, zeta potential of −31.5 ± 2.6 mV, EE% of 76.9 ± 2.5%, and a pH-responsive behavior in two different pHs (5.4 and 7.4). In-silico evaluations showed that MTX intended to make a strong hydrogen bond with Span 60 compartments involving N2 and O4 atoms in glutamic acid and N7 atom in pteridine ring moieties, respectively. The cytotoxic effects of free and pH-MTX/Nio were assessed against MCF7 and HUVECs. Compared with free MTX, we found significantly lower IC50s when MCF7 cells were treated with niosomal MTX (84.03 vs. 9.464 µg/mL after 48 h, respectively). Moreover, lower cell killing activity was observed for this formulation in normal cells. The pH-MTX/Nio exhibited a set of morphological changes in MCF7 cells observed during cell death. In-vivo results demonstrated that intraperitoneal administration of free MTX (2 mg/kg) after six weeks caused a significant increase in serum blood urea nitrogen (BUN), serum creatinine, and serum malondialdehyde (MDA) levels of rats compared to the normal control rats. Treatment with 2 and 4 mg/kg doses of pH-MTX/Nio significantly increased serum BUN, serum creatinine, and serum lipid peroxidation. Still, the safety profile of such formulations in healthy cells/tissues should be further investigated.

Synthesis and Molecular Docking Studies of some Pyrano[2,3-c] Pyrazole as an Inhibitor of SARS-Coronavirus 3CL Protease

The widespread global COVID-19 pandemic due to the lack of specific treatment and the urgent situation requires the use of all resources to remedy this scourge. The current study aimed to use molecular docking tools to find potential drug candidates for treatment. The pyrano[2,3-c] pyrazole 5(a-e) was targeted against the Main protease (Mpro), which plays a vital role in the replication and transcription of the Corona viral genome. The 3CL Protease (PDB ID 6LU7) was modeled, and the compounds were docked using Autodock Vina software, and ADMET data have been studied. All synthesized compounds were well engaged into the active site of the main protease with strong hydrogen bond interaction and a good score of energy. The 5b have been classed as the best inhibitor with an energy score of -6.2 kcal/mol, similar to the one given by chloroquine (-6.2Kcal/mol). Moreover, the molecular interaction studies showed that protease structure had multiple active site residues for all studied compounds. Our finding confirms the potential of these derivatives as lead compounds against the selected target protein of coronavirus, which needs further analysis and dynamic simulation studies to propose then develop a new antiviral treatment.

Spectroscopic Identification of Hydrogen Bond Vibrations and Quasi-Isostructural Polymorphism in N-Salicylideneaniline

The ortho-hydroxy aryl Schiff base 2-[(E)-(phenylimino)methyl]phenol and its deutero-derivative have been studied by the inelastic incoherent neutron scattering (IINS), infrared (IR) and Raman experimental methods, as well as by Density Functional Theory (DFT) and Density-Functional Perturbation Theory (DFPT) simulations. The assignments of vibrational modes within the 3500–50 cm−1 spectral region made it possible to state that the strong hydrogen bond in the studied compound can be classified as the so-called quasi-aromatic bond. The isotopic substitution supplemented by the results of DFT calculations allowed us to identify vibrational bands associated with all five major hydrogen bond vibrations. Quasi-isostructural polymorphism of 2-[(E)-(phenylimino)methyl]phenol (SA) and 2-[(E)-(phenyl-D5-imino)methyl]phenol (SA-C6D5) has been studied by powder X-ray diffraction in the 20–320 K temperature range.

Plasmonic photothermal release of docetaxel by gold nanoparticles incorporated onto halloysite nanotubes with conjugated 2D8-E3 antibodies for selective cancer therapy

Background Applied nanomaterials in targeted drug delivery have received increased attention due to tangible advantages, including enhanced cell adhesion and internalization, controlled targeted release, convenient detection in the body, enhanced biodegradation, etc. Furthermore, conjugation of the biologically active ingredients with the drug-containing nanocarriers (nanobioconjugates) has realized impressive opportunities in targeted therapy. Among diverse nanostructures, halloysite nanotubes (NHTs) with a rolled multilayer structure offer great possibilities for drug encapsulation and controlled release. The presence of a strong hydrogen bond network between the rolled HNT layers enables the controlled release of the encapsulated drug molecules through the modulation of hydrogen bonding either in acidic conditions or at higher temperatures. The latter can be conveniently achieved through the photothermal effect via the incorporation of plasmonic nanoparticles. Results The developed nanotherapeutic integrated natural halloysite nanotubes (HNTs) as a carrier; gold nanoparticles (AuNPs) for selective release; docetaxel (DTX) as a cytotoxic anticancer agent; human IgG1 sortilin 2D8-E3 monoclonal antibody (SORT) for selective targeting; and 3-chloropropyltrimethoxysilane as a linker for antibody attachment that also enhances the hydrophobicity of DTX@HNT/Au-SORT and minimizes DTX leaching in body’s internal environment. HNTs efficiently store DTX at room temperature and release it at higher temperatures via disruption of interlayer hydrogen bonding. The role of the physical expansion and disruption of the interlayer hydrogen bonding in HNTs for the controlled DTX release has been studied by dynamic light scattering (DLS), electron microscopy (EM), and differential scanning calorimetry (DSC) at different pH conditions. HNT interlayer bond disruption has been confirmed to take place at a much lower temperature (44 °C) at low pH vs. 88 °C, at neutral pH thus enabling the effective drug release by DTX@HNT/Au-SORT through plasmonic photothermal therapy (PPTT) by light interaction with localized plasmon resonance (LSPR) of AuNPs incorporated into the HNT pores. Conclusions Selective ovarian tumor targeting was accomplished, demonstrating practical efficiency of the designed nanocomposite therapeutic, DTX@HNT/Au-SORT. The antitumor activity of DTX@HNT/Au-SORT (apoptosis of 90 ± 0.3%) was confirmed by in vitro experiments using a caov-4 (ATCC HTB76) cell line (sortilin expression > 70%) that was successfully targeted by the sortilin 2D8-E3 mAb, tagged on the DTX@HNT/Au. Graphic abstract