Structural and Computational Studies of Cobalt(II) and Copper(II) Complexes with Aromatic Heterocyclic Ligand

Two coordination complexes, a cobalt(II) complex tris(1,10-phenanthroline)-cobalt perchlorate hydrate, [Co(phen)3]·(ClO4)2·H2O(1), and a copper(II) complex tris(1,10-phenanthroline)-copper perchlorate 4-bromo-2-{[(naphthalene-1-yl)imino]methyl}phenol hydrate, [Cu(phen)3]·(ClO4)2·HL·[O] (2), [where, phen = 1,10-phenathroline as aromatic heterocyclic ligand, HL = 4-bromo-2-((Z)-(naphthalene-4-ylimino) methyl) phenol] have been synthesized and structurally characterized. Single crystal X-ray analysis of both complexes has revealed the presence of a distorted octahedral geometry around cobalt(II) and copper(II) ions. density functional theory (DFT)-based quantum chemical calculations were performed on the cationic complex [Co(phen)3]2+ and copper(II) complex [Cu(phen)3]2+ to get the structure property relationship. Hirshfeld surface and 2-D fingerprint plots have been explored in the crystal structure of both the metal complexes. To find potential SARS-CoV-2 drug candidates, both the complexes were subjected to molecular docking calculations with SARS-CoV-2 virus (PDB ID: 7BQY and 7C2Q). We have found stable docked structures where docked metal chelates could readily bound to the SARS-CoV-2 Mpro. The molecular docking calculations of the complex (1) into the 7C2Q-main protease of SARS-CoV-2 virus revealed the binding energy of −9.4 kcal/mol with a good inhibition constant of 1.834 µM, while complex (2) exhibited the binding energy of −9.0 kcal/mol, and the inhibition constant of 1.365 µM at the inhibition binding site of receptor protein. Overall, our in silico studies explored the potential role of cobalt(II) complex (1), and copper(II) complex (2) complex as the viable and alternative therapeutic solution for SARS-CoV-2.

Computational study of 2D photonic crystal based biosensor for SARS-COV-2 detection

A computational study to design a 2D-photonic crystal (PC) structure with a fluorescence-based biosensor has been demonstrated for the detection of the severe acute respiratory syndrome corona virus 2 (SARS-COV-2) virus in the lungs. The proposed sensor can detect the different concentrations of the virus without any pretreatment of the sample. The virus detection is performed by measuring the mid-gap wavelength from the dispersion diagram and a redshift in the mid-gap wavelength has been observed as the concentration of virus increases in the lung tissue. The plane wave expansion method is used to determine the dispersion diagram of the proposed PC. The interaction of incident light with the proposed PC-based biosensor has been analyzed to evaluate the shift in the mid-gap wavelength. A maximum sensitivity of about 1459.3 nm/RIU is obtained for r/a = 0.45 with a mid-gap wavelength shift of 145.93 nm at n net = 1.49 concentration of SARS-COV-2. Moreover, a very small detection time has been observed with the proposed device as compared to conventional methods. This study provides a simple process to detect the presence of a virus within a short period and could be helpful in the development of a direct and easy-to-use portable detection kit in the future. © 2023 IOP Publishing Ltd.

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.

Therapeutic Properties of Vanadium Complexes

Vanadium is a hard, silver-grey transition metal found in at least 60 minerals and fossil fuel deposits. Its oxide and other vanadium salts are toxic to humans, but the toxic effects depend on the vanadium form, dose, exposure duration, and route of intoxication. Vanadium is used by some life forms as an active center in enzymes, such as the vanadium bromoperoxidase of ocean algae and nitrogenases of bacteria. The structure and biochemistry of vanadate resemble those of phosphate, hence vanadate can be regarded as a phosphate competitor in a variety of biochemical enzymes such as kinases and phosphatases. In this review, we describe the biochemical pathways regulated by vanadium compounds and their potential therapeutic benefits for a range of disorders including type 2 diabetes, cancer, cardiovascular disease, and microbial pathology.

New nickel(ii) Schiff base complexes as potential tools against SARS-CoV-2 Omicron target proteins: an in silico approach

Herein, we report the in silico design and synthesis of two new nickel(ii) coordination complexes, viz., [Ni(L-1)][(PPh3)]DMF (1) and [Ni(L-2)] (2), based on Schiff bases derived from the 2-hydroxy-1-naphthaldehyde moiety (where, (LH2)-H-1 = (E)-3-(((5-chloro-2-hydroxyphenyl)imino)methyl)naphthalene-2-ol), ((LH2)-H-2 = 2,2 & PRIME;-((1E,1 & PRIME;E)-(ethane-1,2-diylbis(azaneylylidene))bis(methaneylylidene))bis(naphthalen-2-ol)), PPh3 = (triphenylphosphine). The synthesized ligands (LH2)-H-1 and (LH2)-H-2 were coordinated to Ni(ii) ions through the tridentate-ONO and tetradentate-N2O2 donor atoms, respectively. The newly synthesized complexes were fully characterized using X-ray crystallography analysis. The synthesized complexes (1) and (2) crystallized in the triclinic and monoclinic crystal system with the P1 and P21/c space group, respectively, and exhibited a square planar geometry around the Ni(ii) ions. Computational approaches were employed to determine the structure-property relationship of the complexes. Hirshfeld surface analysis was also performed to investigate intermolecular interactions in the crystal systems. The strength of the interaction and 3D topology of crystal packing were visualized through an energy framework. To gain insights into the potential application of Ni(ii) complexes as effective SARS-CoV-2 Omicron inhibitors, we performed the following docks (a) Ni(ii) complexes with S protein from original SARS-CoV-2 (PDB ID: 7CWO), (b) Ni(ii) complexes with selected Omicron targets (PDB ID: 7QTK and 7WK8) and (c) controls ivermectin and levosalbutamol with the original SARS-CoV-2 spike protein and the Omicron S proteins. The synthesized Ni(ii) complexes (1) and (2) showed good docking results with the S protein of SARS-CoV-2, where the binding energies (& UDelta;G) and respective K-i (inhibition constants) correlation values are -7.38 (3.87 mu M) and -8.82 (341.77 nM), respectively. The molecular docking results revealed that the synthesized complexes (1) and (2) with the SARS-CoV-2 Omicron target protein (PDB ID: 7QTK) resulted the binding energy (& UDelta;G) of -7.46 kcal mol(-1) with an inhibition constant (K-i) of 3.39 mu M and binding energy (& UDelta;G) of -7.56 kcal mol(-1) with an inhibition constant (K-i) of 2.89 mu M, respectively. Similarly, the synthesized Ni(ii) complexes (1) and (2) with the SARS-CoV-2 Omicron target protein (PDB ID: 7WK8) exhibited the binding energy (& UDelta;G) and inhibition constant (K-i) of -7.03 kcal mol(-1) and 7.08 mu M and -7.89 kcal mol(-1) and 1.64 mu M, respectively. It was predicted that ivermectin shows a larger binding energy (& UDelta;G) for S proteins compared to levosalbutamol after molecular docking. Further, in silico ADMET to predict the drug-likeness behaviour and pharmacokinetic response of the synthesized complexes was also explored. Overall, the present study suggests that nickel(ii) complexes can be considered as potential therapeutic drugs against the Omicron target protein of SARS-CoV-2.

Pre- and Post-publication Verification for Reproducible Data Mining in Macromolecular Crystallography.

Like an article narrative is deemed by an editor and referees to be worthy of being a version of record on acceptance as a publication, so must the underpinning data also be scrutinized before passing it as a version of record. Indeed without the underpinning data, a study and its conclusions cannot be reproduced at any stage of evaluation, pre- or post-publication. Likewise, an independent study without its own underpinning data also cannot be reproduced let alone be considered a replicate of the first study. The PDB is a modern marvel of achievement providing an organized open access to depositor and user of the data held there opening numerous applications. Methods for modeling protein structures and for determination of structures are still improving their precision, and artifacts of the method exist. So their accuracy is realized if they are reproduced by other methods. It is on such foundations that reproducible data mining is based. Data rates are expanding considerably be they at synchrotrons, the X-ray free electron lasers (XFELs), electron cryomicroscopes (cryoEM), or at the neutron facilities. The work of a person as a referee or user with a narrative and its underpinning data may well be complemented in future by artificial intelligence with machine learning, the former for specific refereeing and the latter for the more general validation, both ideally before publication. Examples are described involving rhenium theranostics, the anti-cancer platins and the SARS-CoV-2 main protease.

Synthesis and characterization of novel copper(II) complexes as potential drug candidates against SARS-CoV-2 main protease

Two novel copper(II) Schiff base complexes, [Cu(L-1)(2)] (1) and [Cu(L-2)(CH3OH)(Cl)] (2) of [(Z)-(5-chloro-2-((3,5-dichloro-2-hydroxybenzylidene)amino)phenyl)(phenyl)methanone ((LH)-H-1) and (Z)-(2((5-bromo-2-hydroxybenzylidene)amino-5-chlorophenyl)(phenyl)methanone)((LH)-H-2)], have been designed, synthesized and characterized. The crystal structures of both complexes were solved by single-crystal X-ray analysis, which revealed that complex (1) has a square planar geometry with a tetrahedral distortion, while complex (2) exhibits a square pyramid structure with distortion geometry. DFT calculations were performed on the complexes to investigate the structure-property relationship. Hirshfeld surface analyses have also been explored in the crystal structure of complexes. Additionally, their potential applications against the SARS-COV-2 virus were explored by in silico docking studies. We found stable docked structures wherein docked copper(ii) complexes (1) and (2) could readily bind to the viral proteins (PDB ID: 7BUY and 7BRP) of the SARS-CoV-2 main protease (M-pro) active-site region. The molecular docking calculations of complex (1) into the main protease of SARS-CoV-2 (PDB ID: 7BUY) revealed a binding energy of -9.8 kcal mol(-1) with an inhibition constant of 4.235 mu M, whereas that of complex (2) with SARS-CoV-2 resulted in a binding energy of -9.3 kcal mol(-1) and an inhibition constant of 3.152 mu M. Similarly, copper complexes (1) and (2) with SARS-CoV-2 main protease (PDB ID: 7BRP) exhibited binding energy and inhibition constant of -8.7 kcal mol(-1) and 2.585 mu M;-8.2 kcal mol(-1) and 2.359 mu M, respectively, at the inhibition binding site of the receptor protein. Overall, our in silico studies explored the potential role of copper complexes, which would offer new drug candidates against SARS-CoV-2.

Potential applicability of Schiff bases and their metal complexes during COVID-19 pandemic - a review

The rapid growth and revolution in the area of emerging therapeutics has been able to save the life of millions of patients globally. Besides these developments, the microbes are consistently struggling for their own survival and hence becoming quite more sturdy and incurable to existing drugs. Covid-19 virus and Black Fungus are recent examples of failure of medical preparations and strength of these viruses beyond the imagination of medical practitioners. Henceforth the study has made an extensive survey of exiting literature on heterocyclic schiff bases and their transition metal complexes to look for their potential applicability as antimicrobial agents. The inherent physiognomies of the essential properties of these transition metal complexes including thermodynamic, kinetic and chelating are comparatively modifiable as per requirements. The study has found that the biological applications of these transition metal complexes are well suited to be used as antibacterial and antifungal agents.

The development of Nanosota-1 as anti-SARS-CoV-2 nanobody drug candidates.

Combating the COVID-19 pandemic requires potent and low-cost therapeutics. We identified a series of single-domain antibodies (i.e., nanobody), Nanosota-1, from a camelid nanobody phage display library. Structural data showed that Nanosota-1 bound to the oft-hidden receptor-binding domain (RBD) of SARS-CoV-2 spike protein, blocking viral receptor angiotensin-converting enzyme 2 (ACE2). The lead drug candidate possessing an Fc tag (Nanosota-1C-Fc) bound to SARS-CoV-2 RBD ~3000 times more tightly than ACE2 did and inhibited SARS-CoV-2 pseudovirus ~160 times more efficiently than ACE2 did. Administered at a single dose, Nanosota-1C-Fc demonstrated preventive and therapeutic efficacy against live SARS-CoV-2 infection in both hamster and mouse models. Unlike conventional antibodies, Nanosota-1C-Fc was produced at high yields in bacteria and had exceptional thermostability. Pharmacokinetic analysis of Nanosota-1C-Fc documented an excellent in vivo stability and a high tissue bioavailability. As effective and inexpensive drug candidates, Nanosota-1 may contribute to the battle against COVID-19.

Co-crystallization and structure determination: An effective direction for anti-SARS-CoV-2 drug discovery.

Safer and more-effective drugs are urgently needed to counter infections with the highly pathogenic SARS-CoV-2, cause of the COVID-19 pandemic. Identification of efficient inhibitors to treat and prevent SARS-CoV-2 infection is a predominant focus. Encouragingly, using X-ray crystal structures of therapeutically relevant drug targets (PLpro, Mpro, RdRp, and S glycoprotein) offers a valuable direction for anti-SARS-CoV-2 drug discovery and lead optimization through direct visualization of interactions. Computational analyses based primarily on MMPBSA calculations have also been proposed for assessing the binding stability of biomolecular structures involving the ligand and receptor. In this study, we focused on state-of-the-art X-ray co-crystal structures of the abovementioned targets complexed with newly identified small-molecule inhibitors (natural products, FDA-approved drugs, candidate drugs, and their analogues) with the assistance of computational analyses to support the precision design and screening of anti-SARS-CoV-2 drugs.

'All That Glitters Is Not Gold': High-Resolution Crystal Structures of Ligand-Protein Complexes Need Not Always Represent Confident Binding Poses.

Our understanding of the structure-function relationships of biomolecules and thereby applying it to drug discovery programs are substantially dependent on the availability of the structural information of ligand-protein complexes. However, the correct interpretation of the electron density of a small molecule bound to a crystal structure of a macromolecule is not trivial. Our analysis involving quality assessment of ~0.28 million small molecule-protein binding site pairs derived from crystal structures corresponding to ~66,000 PDB entries indicates that the majority (65%) of the pairs might need little (54%) or no (11%) attention. Out of the remaining 35% of pairs that need attention, 11% of the pairs (including structures with high/moderate resolution) pose serious concerns. Unfortunately, most users of crystal structures lack the training to evaluate the quality of a crystal structure against its experimental data and, in general, rely on the resolution as a 'gold standard' quality metric. Our work aims to sensitize the non-crystallographers that resolution, which is a global quality metric, need not be an accurate indicator of local structural quality. In this article, we demonstrate the use of several freely available tools that quantify local structural quality and are easy to use from a non-crystallographer's perspective. We further propose a few solutions for consideration by the scientific community to promote quality research in structural biology and applied areas.

A Therapeutic Non-self-reactive SARS-CoV-2 Antibody Protects from Lung Pathology in a COVID-19 Hamster Model.

The emergence of SARS-CoV-2 led to pandemic spread of coronavirus disease 2019 (COVID-19), manifesting with respiratory symptoms and multi-organ dysfunction. Detailed characterization of virus-neutralizing antibodies and target epitopes is needed to understand COVID-19 pathophysiology and guide immunization strategies. Among 598 human monoclonal antibodies (mAbs) from 10 COVID-19 patients, we identified 40 strongly neutralizing mAbs. The most potent mAb, CV07-209, neutralized authentic SARS-CoV-2 with an IC50 value of 3.1 ng/mL. Crystal structures of two mAbs in complex with the SARS-CoV-2 receptor-binding domain at 2.55 and 2.70 Å revealed a direct block of ACE2 attachment. Interestingly, some of the near-germline SARS-CoV-2-neutralizing mAbs reacted with mammalian self-antigens. Prophylactic and therapeutic application of CV07-209 protected hamsters from SARS-CoV-2 infection, weight loss, and lung pathology. Our results show that non-self-reactive virus-neutralizing mAbs elicited during SARS-CoV-2 infection are a promising therapeutic strategy.

Identification of 22 N-glycosites on spike glycoprotein of SARS-CoV-2 and accessible surface glycopeptide motifs: Implications for vaccination and antibody therapeutics.

Coronaviruses hijack human enzymes to assemble the sugar coat on their spike glycoproteins. The mechanisms by which human antibodies may recognize the antigenic viral peptide epitopes hidden by the sugar coat are unknown. Glycosylation by insect cells differs from the native form produced in human cells, but insect cell-derived influenza vaccines have been approved by the US Food and Drug Administration. In this study, we analyzed recombinant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein secreted from BTI-Tn-5B1-4 insect cells, by trypsin and chymotrypsin digestion followed by mass spectrometry analysis. We acquired tandem mass spectrometry (MS/MS) spectrums for glycopeptides of all 22 predicted N-glycosylated sites. We further analyzed the surface accessibility of spike proteins according to cryogenic electron microscopy and homolog-modeled structures and available antibodies that bind to SARS-CoV-1. All 22 N-glycosylated sites of SARS-CoV-2 are modified by high-mannose N-glycans. MS/MS fragmentation clearly established the glycopeptide identities. Electron densities of glycans cover most of the spike receptor-binding domain of SARS-CoV-2, except YQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQ, similar to a region FSPDGKPCTPPALNCYWPLNDYGFYTTTGIGYQ in SARS-CoV-1. Other surface-exposed domains include those located on central helix, connecting region, heptad repeats and N-terminal domain. Because the majority of antibody paratopes bind to the peptide portion with or without sugar modification, we propose a snake-catching model for predicted paratopes: a minimal length of peptide is first clamped by a paratope and sugar modifications close to the peptide either strengthen or do not hinder the binding.