The Non-Covalent Interactions index: From biology to chemical reactivity and solid-state

The Non-Covalent Interaction (NCI) index has become a versatile tool for analyzing the presence and strength of localized and delocalized interactions in systems of interest to diverse areas such as biochemistry, reactivity, and solid state. Furthermore, it can be applied to promolecular, ab initio or even experimental electron densities, making it an even more flexible method. In this chapter, we demonstrate some of these NCI capacities by employing it in three representative cases: (a) Interaction between the spike protein of some early variants of the SARS-CoV-2 virus with selected potential inhibitors. (b) The ring-opening metathesis polymerization of two norbornene derivatives, mediated by a ruthenium-alkylidene catalyst. (c) Effect of π-electron delocalization in the structural and electronic changes on the noncovalent interactions in two quinone crystals. These cases are illustrative of the application of NCI to study ligand-protein interactions, the interplay of inter and intramolecular forces in reaction pathways, and crystal packing, respectively. Moreover, we show the suitability of using different methods for obtaining the electron density in each example. © 2023 Elsevier Inc. All rights reserved.

Opportunities for predicting adverse pregnancy outcomes in severe COVID-19.

Aim: to asses an opportunity for predicting an unfavorable perinatal and maternal pregnancy outcome in severe novel coronavirus infection (NCI) COVID-19. Materials and Methods. A retrospective comparative study of the course and outcomes of pregnancies was performed in 40 patients with a gestational age of 22-42 weeks who had severe and extremely severe COVID-19 in 2021. The main group included 21 cases with an extremely severe course of the disease resulting in maternal mortality;the comparison group consisted of 19 patients with severe COVID-19 who successfully completed pregnancy. The diagnosis of NCI COVID-19 was confirmed in all cases by identifying SARS-CoV-2 RNA by polymerase chain reaction in a nasopharyngeal swab. During the study, all patients (during hospitalization, at the peak of the disease and before death/discharge from the hospital) underwent a comprehensive anamnestic, clinical and laboratory-instrumental examination. There were analyzed clinical blood test, biochemical parameters - lactate dehydrogenase (LDH), alanine aminotransferase, aspartate aminotransferase, creatinine, glucose, total bilirubin, total protein;coagulation parameters - prothrombin level according to Quick and fibrinogen, activated partial thromboplastin time, international normalized ratio;the level of C-reactive protein, procalcitonin, D-dimer, interleukin-6 (IL-6);ultrasound examination was performed during pregnancy (fetometry, placentometry), dopplerometry of uteroplacental blood flow and ultrasound of the pelvic organs, as well as pathomorphological placenta examination. Results. In patients who died from extremely severe NCI COVID-19 (main group), the course of the infection was accompanied by developing of respiratory distress (RD) degree III (chi2 = 12.84;p <= 0.05), and a progressive deterioration in mother's condition and/or fetal distress was an indication for emergency delivery by caesarean section (CS). The course of severe NCI COVID-19 in patients with a favorable outcome (comparison group), as a rule, was accompanied by the development of RD grade I and/or II;most of them were also delivered by CS on an emergency/urgent basis. Predictors of rapid progression of severe NCI COVID-19 in the main group were identified: subfebrile body temperature at the initial stages skewing to high fever during treatment instead of rapid temperature normalization (chi2 = 5.41;p <= 0.05;odds ratio (OR) = 5.0;95 % confidence interval (CI) = 1.23-20.3);lack of leukocytosis at the initial stages (chi2 = 4.91;p <= 0.05;OR = 50;95 % CI = 5.43-460.54) with rapidly increased leukocyte count with persistent stagnation in dynamics until death (chi2 = 19.79, p <= 0.05, OR = 50;95 % CI = 5.43-460.54);severe lymphopenia (chi2 = 8.09;p <= 0.05;OR = 7.29;95 % CI = 1.74-30.56), neutrophilia (chi2 = 10.17;p <= 0.05;OR = 10.29;95 % CI = 2.21-47.84);high LDH values (chi2 = 17.99;p <= 0.05;OR = 31.88;95 % CI = 5.09-199.49);increased IL-6 level at the peak of the disease (chi2 = 9.66;p <= 0.05;OR = 18;95 % CI = 1.99-162.62) and in dynamics, as well as stably high D-dimer values (chi2 = 9.53, p <= 0.05;OR = 11.33;95 % CI = 2.07-62.11). Conclusion. Significant changes observed in clinical and laboratory examination were identified, which reliably reflect the degree of patients' state, to be interpreted as predictors of adverse pregnancy outcomes during NCI COVID-19 and as a potentially justified serious reason for making a decision in the light of timely delivery aimed at a favorable outcome for mother and child. Timely delivery, carried out within the time limits for enabling adequate compensatory capabilities of the pregnant woman's body, demonstrates a rapid normalization of the main laboratory parameters.Copyright © 2023 IRBIS LLC. Pravo. All rights reserved.

Computational studies on the design of NCI natural products as inhibitors to SARS-CoV-2 main protease.

The pandemic coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in more than 5 million deaths globally. Currently there are no effective drugs available to treat COVID-19. The viral protease replication can be blocked by the inhibition of main protease that is encoded in polyprotein 1a and is therefore a potential protein target for drug discovery. We have carried out virtual screening of NCI natural compounds followed by molecular docking in order to identify hit molecules as probable SARS-CoV-2 main protease inhibitors. The molecular dynamics (MD) simulations of apo form in complex with N3, α-ketoamide and NCI natural products was used to validate the screened compounds. The MD simulations trajectories were analyzed using normal mode analysis and principal component analysis revealing dynamical nature of the protein. These findings aid in understanding the binding of natural products and molecular mechanisms of SARS-CoV-2 main protease inhibition.Communicated by Ramaswamy H. Sarma.

4-(4-methoxyphenyl)-6-methyl-3-phenyl-4H-1,2,4-oxadiazin-5(6H)-one: Synthesis, crystal structure, Hirshfeld surface analysis, noncovalent, ADMET studies and biological evaluation

Oxadiazines are heterocyclic compounds containing two nitrogen and one oxygen atom in a six-membered ring. The synthesis and crystal structure of 4-(4-methoxyphenyl)-6-methyl-3-phenyl-4H-1,2,4-oxadiazin-5(6H)-one (MPMP-OXA) was reported. The organic crystal structure of the synthesized compound was fully characterized by various spectroscopic techniques (Fourier Transform Infrared Spectroscopy, NMR and LC/MS-TOF) and single-crystal X-ray diffraction studies. The MPMP-OXA crystal structure crystallizes in the triclinic system and space group P-1 with a = 5.9395(15) Å, b = 11.471(3) Å, c = 11.901(3) Å, α = 70.075(4)°, β = 83.454(4)°, γ = 78.016(4)°, V = 744.9(3) Å3, Z = 2 cell parameters. This work is aimed to study the weak interactions in the crystal packing of a new synthesized oxadiazine derivate. The contributions of the most important intermolecular interactions in the crystal structure were investigated by 3D-Hirshfeld surface (HS) and 2D-fingerprint analysis. The C[sbnd]H···O interactions as the most important contributors to the crystal packing between the oxygen of the oxadiazine ring and the hydrogen atom of phenyl ring appear as bright red spots visible on the HS surface. The hydrogen-bonded interaction of MPMP-OXA has been investigated using noncovalent interactions approach. The molecular docking studies for the synthesized compound were performed to gain insight into the inhibition nature of this molecule against DNA Gyrase B Candida and 3-chymotrypsin-like protease (SARS-CoV main protease) proteins and resulted in good activities for new anti-agents. Lastly, Bioavailability, druggability as well as absorption, distribution, metabolism, excretion, and toxicity parameters (ADMET), and gastrointestinal absorption (BOILED-Egg method) properties of newly synthesized compound using smile codes were performed in detail. © 2023 Elsevier B.V.

The investigation of modification in structural flexibility and coordination modes in a solvent free β-diketone Cu(II) complex by crystal structure and DFT studies

Coordination-driven self-assembly in inorganic complexes is a viable methodology to construct supramolecular coordination complexes. Crystal engineering of β-diketone Cu(II) coordination complexes can be achieved via the host-guest complexation method. The effect of metal-ligand interactions (coordination polyhedra) on the supramolecular framework has been analysed by crystal structure and computational studies. A new crystal form of a Cu(II) complex with 4,4,4-trifluoro-naphthyl butanedione has been identified and characterized using various spectroscopic techniques. X-ray diffraction studies unveiled that complex 1, [Cu(TFNB)2], crystallized in the monoclinic (P21/n) space group and its solvent-induced crystal forms, complex 2, [Cu(TFNB)2DMSO] (Database Identifier: IVAKIC), and complex 3, [Cu(TFNB)2DMF] (Database Identifier: ZOCHOR), which were reported earlier, are in the triclinic (P 1¯) crystal system. The previously reported crystal forms (complexes 2 and 3) are examples of a single crystal coordinated solvent exchange (SCCSE) transformation. In complex 1, the β-diketone molecules are attached to the metal ion in an equatorial form with a perfect square planar geometry, whilst complexes 2 and 3 feature a slightly distorted square pyramidal geometry with chelated donor oxygen atoms of the β-diketone ligands in equatorial sites and the crystallizing DMSO and DMF solvents are apically coordinated to the metal centre, respectively. Interestingly, the oxygen donors of the β-diketone ligands in complex 1 are inclined in a trans configuration, whereas in the solvent-induced pseudopolymorphic forms of complexes 2 and 3, a cis configuration is observed. The variation in the supramolecular framework with the coordination geometry in different crystal forms is analysed using the crystal structures and compared with quantum computational (Hirshfeld surface, enrichment ratio, energy framework, NCI index model and DFT) results. Molecular docking analysis was performed for all the complexes against the SARS-CoV2 main protease to explore the structure-property relationship.

Antiviral effect of Fufang yinhua jiedu (FFYH) granules against coronavirus and its potential mechanism

To investigate the effect of Fufang yinhua jiedu (FFYH) granules against coronavirus and its potential mechanism, we used Huh7, Huh7.5, H460, and C3A cell lines as in vitro models to evaluate the cytotoxicity and antiviral activity of FFYH by observation of cell pathogenic effect (CPE);and then the inhibitory effect of FFYH on the transcription expression of coronavirus RNA and inflammatory factor mRNA were evaluated by quantitive reverse transcription PCR (qRT-PCR);finally, the inhibitory effect of FFYH on the expression of coronavirus protein and its underlying mechanism against coronavirus were investigated by Western blot and immunofluorescence. Our results indicated that 50% toxic concentration (TC50) FFYH on Huh7, Huh7.5, H460, and C3A cells were 2 035.21, 5 245.69, 2 935.28 and 520 µg·mL-1, respectively;50% inhibitory concentration (IC50) of FFYH on HCoV-229E in Huh7 and Huh7.5 cells were 438.16 and 238.54 µg·mL-1 with safety index (SI) of 4.64 and 21.99, respectively;IC50 of FFYH on HCoV-OC43 in H460 cells was 165.13 µg·mL-1 with SI of 17.78. Moreover, FFYH not only could inhibit the replication of coronaviruses (HCoV-OC43 and HCoV-229E) through inhibiting the transcription of viral RNA and the expression of viral protein, but also effectively suppress the expression of inflammatory factors interleukin-6 (IL-6), tumor necrosis factor α (TNF-α) and interleukin-8 (IL-8) at mRNA level caused by coronaviruses, which might be associated with the inhibitory effect of FFYH on mitogen-activated protein kinase (MAPK) pathway and the nuclear translocation of nuclear transcription factor-κB (NF-κB). In summary, our results demonstrated that FFYH exhibited a good in vitro anti-coronavirus effect, which provides a theoretical basis for its clinical use in the treatment of anti-coronavirus pneumonia.

MOLECULAR DETERMINANTS of SARS-CoV-2 CELLULAR TROPISM in VITRO

Background: Lung cell lines to model SARS-CoV-2 replication in vitro are greatly limited hampering the rigorous study of SARS-CoV-2-host interactions. We analyzed a panel of 10 airway cell lines with various levels of ACE2 expression to identify models of SARS-CoV-2 infection. We found that none of the ACE2 expressing cell lines supported replication, whereas the H522 human lung adenocarcinoma cells were naturally permissive to SARS-CoV-2 infection despite detectable expression of ACE2. We confirmed that SARS-CoV-2 replication is indeed completely independent of ACE2 in H522s but dependent on heparan sulfates and the E484D substitution within the Spike. Further, we show that many of the ACE2 positive non-permissive cell lines express high basal levels of interferon-stimulated genes, which can be overcome by inhibition of the JAK/STAT pathway or by ACE2 overexpression. Together, our findings highlight ACE2-independent pathways can control the cellular tropism of SARS-CoV-2. Methods: Conventional molecular virology assays have been conducted to study the permissiveness of a panel of 10 cell lines expressing various levels of ACE2. ACE2 independence of SARS-CoV-2 replication was validated by antibody blocking, Fc-ACE2 decoy peptide and CRISPR-based approaches in H522 cells. RNA sequencing was used to study the basal level of genes in the type-I IFN pathway in the panel of 10 cell lines, which was further validated by western blotting and qRT-PCR. A panel of 5 cell lines, with varying expression levels of ACE2 and TMPRSS2, were pre-treated with Ruxolitinib, a JAK inhibitor, and infected with SARS-CoV-2 strain 2019-nCoV/USA-WA1/2020 and spike variants. Viral replication was detected through analysis of cell associated RNA Results: H522 human lung adenocarcinoma supports SARS-CoV-2 replication in a completely ACE2-independent manner. Transcriptomic analysis revealed basal high level of expression of interferon response pathway genes in some ACE2-positive cells recalcitrant to SARS-CoV-2 infection. Infection of OE21 and SCC25 cells required blocking of the IFN response pathway or ACE2 overexpression to allow SARS-CoV-2 infection. Conclusion: These findings suggest that SARS-CoV-2 replication can proceed in complete absence of ACE2 and that the innate immunity is a key determinant of SARS-CoV-2 cellular tropism. These findings may explain the complex SARS-CoV-2 pathogenesis in vivo as it shows that factors independent of ACE2 can define cellular tropism.

Synthesis, Vibrational Depictions, IRI Interpretations and Docking Research on Coordination Metal Complex Diaqua Aspartato Zinc (II) Monohydrate using DFT Approach

In this study, the anti-viral metal coordination complex Diaqua aspartato zinc (II) Monohydrate (DAZM) was grown and its functional outcomes were depicted using Infrared and Raman spectra. For the computational calculations, the Gaussian software package with the B3LYP functional method was implemented to find the optimised parameters of DAZM and correlated them with the experimental data. With the aid of the SQM method, scaled wavenumbers for all the modes of vibration have been deliberated from the PED results. The donor-acceptor interactions were studied to inspect the molecular stability and bond strength. HOMO, LUMO and ESP analyses were done using DFT, whereas, the absorption band in the UV–vis spectrum was predicted and compared with the experimental data. The interactions obtained in the coordination compound were investigated through NCI, DORI and IRI analyses. The docking parameters were studied with SARS-CoV-2 spike glycoproteins and the minimum binding energy was calculated. With the aid of Lipinski’s rule, drug likeness test was done for the DAZM molecule and using the ADMET contour the molecule is suggested as a part of medications.

Synthesis, Crystal structure, Hirshfeld surface, DFT and Docking studies of 4-[(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)(phenyl)methyl]-5-methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one

In the present work, 4-[(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)(phenyl)methyl]-5-methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one (BPZ) was synthesized by one pot multicomponent reaction of ethylacetoacetate, phenylhydrazine and benzaldehyde in the presence of Ce-MCM-48 catalyst. The title compound was characterized by FT-IR, 1H NMR, and 13C NMR spectral studies and single crystal XRD technique. The intermolecular contacts of the title compound were studied by Hirshfeld surface (dnorm surfaces and 2D fingerprint plots) analysis whereas an intra-molecular hydrogen bonding interaction was examined through NCI-RDG plot. The geometry of the molecular structure was optimized by using the density functional theory (DFT) at B3LYP/6-311g(d,p) level. Molecular electrostatic potential (MEP), natural bond orbital (NBO) analysis, nonlinear optical properties (NLO) and global chemical reactivity parameters (GCRP) were described through computational method. Further, the molecular docking study was done for title compound with COVID-19 caused protein structure (6LU7, nCoV-SARS-2 Mpro). The study revealed that the significant conventional hydrogen bonding and other interactions were observed between active amino acid residue of nCoV-SARS-2 Mpro and BPZ ligand.

Synthesis, spectroscopic, and computational studies on molecular charge-transfer complex of 2-((2-hydroxybenzylidene) amino)-2-(hydroxymethyl) propane-1, 3-diol with chloranilic acid: Potential antiviral activity simulation of CT-complex against SARS-CoV-2.

An innovative charge-transfer complex between the Schiff base 2-((2-hydroxybenzylidene) amino)-2-(hydroxymethyl) propane-1,3-diol [SAL-THAM] and the π-acceptor, chloranilic acid (CLA) within the mole ratio (1:1) was synthesized and characterized aiming to investigate its electronic transition spectra in acetonitrile (ACN), methanol (MeOH) and ethanol (EtOH) solutions. Applying Job`s method in the three solvents supported the 1:1 (CLA: SAL-THAM) mole ratio complex formation. The formation of stable CT- complex was shown by the highest values of charge-transfer complex formation constants, KCT, calculated using minimum-maximum absorbance method, with the sequence, acetonitrile > ethanol > methanol DFT study on the synthesized CT complex was applied based on the B3LYP method to evaluate the optimized structure and extract geometrical and reactivity parameters. Based on TD-DFT theory, the electronic properties, 1H and 13C NMR, IR, and UV-Vis spectra of the studied system in different solvents showing good agreement with the experimental studies. MEP map described the possibility of hydrogen bonding and charge transfer in the studied system. Finally, a computational approach for screening the antiviral activity of CT - complex towards SARS-CoV-2 coronavirus protease via molecular docking simulation was conducted and confirmed with molecular dynamic (MD) simulation.

Broad-Spectrum In Vitro Antiviral Activity of ODBG-P-RVn: An Orally-Available, Lipid-Modified Monophosphate Prodrug of Remdesivir Parent Nucleoside (GS-441524).

The necessity for intravenous administration of remdesivir confines its utility for treatment of coronavirus disease 2019 (COVID-19) to hospitalized patients. We evaluated the broad-spectrum antiviral activity of ODBG-P-RVn, an orally available, lipid-modified monophosphate prodrug of the remdesivir parent nucleoside (GS-441524), against viruses that cause diseases of human public health concern, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ODBG-P-RVn showed 20-fold greater antiviral activity than GS-441524 and had activity nearly equivalent to that of remdesivir in primary-like human small airway epithelial cells. Our results warrant in vivo efficacy evaluation of ODBG-P-RVn. IMPORTANCE While remdesivir remains one of the few drugs approved by the FDA to treat coronavirus disease 2019 (COVID-19), its intravenous route of administration limits its use to hospital settings. Optimizing the stability and absorption of remdesivir may lead to a more accessible and clinically potent therapeutic. Here, we describe an orally available lipid-modified version of remdesivir with activity nearly equivalent to that of remdesivir against emerging viruses that cause significant disease, including Ebola and Nipah viruses. Our work highlights the importance of such modifications to optimize drug delivery to relevant and appropriate human tissues that are most affected by such diseases.

Tuning the Computational Evaluation of Spectroscopic, ELF, LOL, NCI analysis and Molecular Docking of Novel Anti COVID-19 Molecule 4-Dimethylamino Pyridinium 3, 5-Dichlorosalicylate.

In this work novel antiviral compound 4-(Dimethylamino) Pyridinium 3, 5-dichlorosalicylate was synthesized and characterized by UV-vis, FT-IR, FT-Raman, 1H NMR and 13C NMR spectra. Quantum chemical computations were carried out by Density functional theory methods at B3LYP level. Electronic stability of the compound arising from hyper conjugative interactions and charge delocalization is investigated using natural bond orbital analysis. Assignments of vibrational spectra have been carried out with the aid of Normal coordinate analysis following the SQMFF methodology. TD-DFT approach was applied to assign the electronic transition observed in UV visible spectrum measured experimentally. Frontier molecular orbital energy gap affirms the bioactivity of the molecule and NCI analysis gives information about inter and intra non covalent interactions. ESP recognises the nucleophilic and electrophilic regions of molecule and the chemical implication of molecule was explained using ELF, LOL. The reactive sites of the compound were studied from the Fukui function calculations and chemical descriptors define the reactivity of the molecule. Molecular docking done with SARS and MERS proteins endorses the bioactivity of molecule and drug likeness factors were calculated to comprehend the biological assets of DADS.

MEDT study of the 1,3-DC reaction of diazomethane with Psilostachyin and investigation about the interactions of some pyrazoline derivatives with protease (Mpro) of nCoV-2.

The molecular electronic density theory (MEDT) was invested to elucidate the chemo-, regio- and stereo-selectivity of the 1,3-dipolar cycloaddition between Diazomethane (DZM) and Psilostachyin (PSH). The DFT method at B3LYP/6-31 + G (d,p) level of theory was used. Reactivity indices, transition structures theory, IGM and ELF analysis were employed to reveal the mechanism of the reaction. The addition of DZM to PSH takes place through a one-step mechanism and an asynchronous transition states. Eight possible addition channels of reaction were investigated (addition of C (sp2) to Diazomethane at C4, C5, C6 or C7). The addition of C (sp2) at C5 leading to P1 product is the preferred channel. The addition of ether does not affect the chemo-, regio- and stereo-selectivity of the reaction. Analysis of transfer of charges along the IRC path associated with the P1 product shows a polar character for the studied reaction. We have also used the noncovalent interaction (NCI) which is very helpful to reveal the most favored addition channel of the reaction, by analyzing the weak interactions in different TSs. Finally, we investigate about the potential of inhibition of some pyrazoline compounds against COVID-19-Mpro by performing a molecular docking calculations.

Modelling the structural and reactivity landscapes of tucatinib with special reference to its wavefunction-dependent properties and screening for potential antiviral activity.

HER-2 type breast cancer is one of the most aggressive malignancies found in women. Tucatinib is recently developed and approved as a potential medicine to fight this disease. In this manuscript, we present the gross structural features of this compound and its reactivity and wave function properties using computational simulations. Density functional theory was used to optimise the ground state geometry of the molecule and molecular docking was used to predict biological activity. As the electrons interact with electromagnetic radiations, electronic excitations between different energy levels are analysed in detail using time-dependent density functional theory. Various intermolecular and intermolecular interactions are analysed and reaction sites for attacking electrophiles and nucleophiles identified. Information entropy calculations show that the compound is inherently stable. Docking with COVID-19 proteins show docking score of - 9.42, - 8.93, - 8.45 and - 8.32 kcal/mol respectively indicating high interaction between the drug and proteins. Hence, this is an ideal candidate to study repurposing of existing drugs to combat the pandemic.