Crystal Structure Of Complex Research Articles

Novel Copper(II) Complexes with N4,S-Diallylisothiosemicarbazones as Potential Antibacterial/Anticancer Drugs

The six new copper(II) coordination compounds [Cu(HL1)Cl2] (1), [Cu(HL1)Br2] (2), [Cu(H2O)(L1)(CH3COO)]·1.75H2O (3), [Cu(HL2)Cl2] (4), [Cu(HL2)Br2] (5), [Cu(H2O)(L2)(CH3COO)] (6) were synthesized with 2-formyl- and 2-acetylpyridine N4,S-diallylisothiosemicarbazones (HL1 and HL2). The new isothiosemicarbazones were characterized by NMR, FTIR spectroscopy, and X-ray crystallography ([H2L2]I). All copper(II) coordination compounds were characterized by elemental analysis, FTIR spectroscopy, and molar conductivity of their 1mM methanol solutions. Furthermore, the crystal structure of complex 3 was determined using single-crystal X-ray diffraction analysis. The studied complexes manifest antibacterial and antifungal activities, that in many cases are close to the activity of medical drugs used in this area, and in some cases even exceed them. The complexes 4 and 5 showed the highest indexes of selectivity (280 and 154) and high antiproliferative activity against BxPC-3 cell lines that surpass the activity of Doxorubicin. The complexes 1–3 also manifest antioxidant activities against cation radicals ABTS•+ that are close to that of trolox, the antioxidant agent used in medicine.

Structure of Mycobacterium tuberculosis 1-Deoxy-D-Xylulose 5-Phosphate Synthase in Complex with Butylacetylphosphonate

Stagnation in the development of new antibiotics emphasizes the need for the discovery of drugs with novel modes of action that can tackle antibiotic resistance. Contrary to humans, most bacteria use the methylerythritol phosphate (MEP) pathway to synthesize crucial isoprenoid precursors. 1-deoxy-D-xylulose 5-phosphate synthase (DXPS) catalyzes the first and rate-limiting step of the pathway, making it an attractive target. Alkylacetylphosphonates (alkylAPs) are a class of pyruvate mimicking DXPS inhibitors that react with thiamin diphosphate (ThDP) to form a stable phosphonolactyl (PLThDP) adduct. Here, we present the first M. tuberculosis DXPS crystal structure in complex with an inhibitor (butylacetylphosphonate (BAP)) using a construct with improved crystallization properties. The 1.6 Å structure shows that the BAP adduct interacts with catalytically important His40 and several other conserved residues of the active site. In addition, a glycerol molecule, present in the D-glyceraldehyde 3-phosphate (D-GAP) binding site and within 4 Å of the BAP adduct, indicates that there is space to extend and develop more potent alkylAPs. The structure reveals the BAP binding mode and provides insights for enhancing the activity of alkylAPs against M. tuberculosis, aiding in the development of novel antibiotics.

Dual domain recognition determines SARS-CoV-2 PLpro selectivity for human ISG15 and K48-linked di-ubiquitin

The Papain-like protease (PLpro) is a domain of a multi-functional, non-structural protein 3 of coronaviruses. PLpro cleaves viral polyproteins and posttranslational conjugates with poly-ubiquitin and protective ISG15, composed of two ubiquitin-like (UBL) domains. Across coronaviruses, PLpro showed divergent selectivity for recognition and cleavage of posttranslational conjugates despite sequence conservation. We show that SARS-CoV-2 PLpro binds human ISG15 and K48-linked di-ubiquitin (K48-Ub2) with nanomolar affinity and detect alternate weaker-binding modes. Crystal structures of untethered PLpro complexes with ISG15 and K48-Ub2 combined with solution NMR and cross-linking mass spectrometry revealed how the two domains of ISG15 or K48-Ub2 are differently utilized in interactions with PLpro. Analysis of protein interface energetics predicted differential binding stabilities of the two UBL/Ub domains that were validated experimentally. We emphasize how substrate recognition can be tuned to cleave specifically ISG15 or K48-Ub2 modifications while retaining capacity to cleave mono-Ub conjugates. These results highlight alternative druggable surfaces that would inhibit PLpro function.

Structures of Vac8-containing protein complexes reveal the underlying mechanism by which Vac8 regulates multiple cellular processes

Vac8, a yeast vacuolar protein with armadillo repeats, mediates various cellular processes by changing its binding partners; however, the mechanism by which Vac8 differentially regulates these processes remains poorly understood. Vac8 interacts with Nvj1 to form the nuclear-vacuole junction (NVJ) and with Atg13 to mediate cytoplasm-to-vacuole targeting (Cvt), a selective autophagy-like pathway that delivers cytoplasmic aminopeptidase I directly to the vacuole. In addition, Vac8 associates with Myo2, a yeast class V myosin, through its interaction with Vac17 for vacuolar inheritance from the mother cell to the emerging daughter cell during cell divisions. Here, we determined the X-ray crystal structure of the Vac8-Vac17 complex and found that its interaction interfaces are bipartite, unlike those of the Vac8-Nvj1 and Vac8-Atg13 complexes. When the key amino acids present in the interface between Vac8 and Vac17 were mutated, vacuole inheritance was severely impaired invivo. Furthermore, binding of Vac17 to Vac8 prevented dimerization of Vac8, which is required for its interactions with Nvj1 and Atg13, by clamping the H1 helix to the ARM1 domain of Vac8 and thereby preventing exposure of the binding interface for Vac8 dimerization. Consistently, the binding affinity of Vac17-bound Vac8 for Nvj1 or Atg13 was markedly lower than that of free Vac8. Likewise, free Vac17 had no affinity for the Vac8-Nvj1 and Vac8-Atg13 complexes. These results provide insights into how vacuole inheritance and other Vac8-mediated processes, such as NVJ formation and Cvt, occur independently of one another.

Copper(II)/diiminic complexes based on 2-hydroxybenzophenones: DNA- and BSA-binding studies and antitumor activity against HCT116 and HepG2 tumor cells

Here, we report four new heteroleptic Cu(II) complexes with the formula [Cu(bipy)(2H4MeBz)]NO3 (1), [Cu(phen)(2H4MeBz)]NO3 (2), [Cu(bipy)(2H4OcBz)]NO3 (3) and [Cu(phen)(2H4OcBz)]NO3 (4), where the ligands are 2-hydroxy-4-methoxybenzophenone (2H4MeBz), 2-hydroxy-4-(octyloxy)benzophenone (2H4OcBz), 2,2′-bipiridine (bipy) and 1,10-phenantroline (phen). All compounds present two bidentate ligands, a monoanionic 2-hydroxybenzophenone, forming a six-membered chelate ring and the diiminic ring forming a five-membered chelate ring, as well as one nitrate as counterion located at the axial position, as suggested by the crystal structure of complex 2. Complex/DNA interaction studies were also performed using spectroscopic titration (Kb close to 104 M−1), viscosity, Hoechst 33258 competition, and circular dichroism, revealing a moderate interaction between them. Additionally, complexes 1–4 moderately interact with BSA (Bovine Serum Albumin). The compounds were evaluated against HCT116 (human colon carcinoma) and HepG2 (human hepatocellular carcinoma) cancer cells and against MRC-5 (human lung fibroblast), a noncancer cells. The cytotoxic results suggest that complexes 2 and 4 are more cytotoxic than 1 and 3, showing that the presence of phen ligand may play an important role in increasing the biological effect of the compounds.

Design, synthesis, and biological evaluation of 1,2,4-triazole derivatives as potent antitubercular agents

Inhibition of mycobacterial membrane protein large 3 (MmpL3) thereby affecting the mycolic acid biosynthetic pathway has been proven to be an effective strategy for developing antitubercular drugs. Based on the X-ray crystal structure of MmpL3 inhibitor complexes, a series of novel 1,2,4-triazole derivatives were designed, synthesized and evaluated antitubercular activity against Mtb strain H37Rv. Comprehensive structure–activity relationship exploration resulted in the identification of compounds 21 and 28, which possess potent antitubercular activity against Mtb strain H37Rv [minimum inhibitory concentration (MIC) = 0.03–0.13 µg/mL] and the clinical isolates of multidrug resistance (MDR) and extensive drug resistance (XDR) tuberculosis (MIC = 0.06–1.0 µg/mL). Moreover, compounds 21 and 28 showed neglectable cytotoxicity (IC50 ≥ 32 µg/mL) to the mammalian Vero cells and favorable physicochemical and pharmacokinetic properties according to the in silico absorption, distribution, metabolism and excretion (ADME) prediction. Finally, the potential target of representative 1,2,4-triazole 28 was identified to be MmpL3 using a microscale thermophoresis (MST) assay.

Catalytic activity of a new Cd (II) complex in the peroxidation of cyclohexane and the resulting CdO nanoparticles in the removal of Congo red

A new coordination complex of [Cd (2,2′‐bipyridine)(dipic) (H2O)2]. 7H2O (dipic2− = pyridine 2,6‐dicarboxylate) was synthesized under hydrothermal conditions. The crystal structure of Cd complex was characterized by X‐ray diffraction. The results confirmed that the coordination geometry of Cd2+ is a distorted pentagonal bipyramid. The complex was evaluated as a catalyst for the peroxidation of cyclohexane. The oxidation reaction was performed under mild conditions by hydrogen peroxide at room temperature. In the absence of HNO3, Cd complex exhibits a maximum yield of 31%. CdO nanoparticles were synthesized through thermal analysis of Cd complex and identified by various techniques. The ability of CdO nanoparticles was investigated for the removal of Congo red (CR). The effects of contact time, adsorbent dosage, and pH were evaluated using batch method. Studies have shown that the uptake process is pseudo‐second order. Also, the adsorption isotherm can be well fitted by the Langmuir model, while this process is spontaneous.

X-ray crystallography of mutant GDSL esterase S12A of Photobacterium marinum J15.

GDSL esterase is designated as a member of Family II of lipolytic enzymes known to catalyse the synthesis and hydrolysis of ester bonds. The enzyme possesses a highly conserved motif Ser-Gly-Asn-His in the four conserved blocks I, II, III and V respectively. The enzyme characteristics, such as region-, chemo-, and enantioselectivity, help in resolving the racemic mixture of single-isomer chiral drugs. Recently, crystal structure of GDSL esterase from Photobacterium J15 has been reported (PDB ID: 5XTU) but not in complex with substrate. Therefore, GDSL in complex with substrate could provide insights into the binding mode of substrate towards inactive form of GDSL esterase (S12A) and identify the hot spot residues for the designing of a better binding pocket. Insight into molecular mechanisms is limited due to the lack of crystal structure of GDSL esterase-substrate complex. In this paper, the crystallization of mutant GDSL esterase (S12A) (PDB ID: 8HWO) and its complex with butyric acid (PDB ID: 8HWP) are reported. The optimized structure would be vital in determining hot spot residue for GDSL esterase. This preliminary study provides an understanding of the interactions between enzymes and hydrolysed p-nitro-phenyl butyrate. The information could guide in the rational design of GDSL esterase in overcoming the medical limitations associated with racemic mixture.

Abstract 3101: Discovery of helical sulfonyl-γ-AApeptides targeting LC3 in cancer cells

Abstract Introduction: Autophagy pathway activation and upregulation is an important mechanism for cancer cell survival upon exposure to chemotherapeutic agents. LC3, a ubiquitin-like protein, plays a key role in the regulation of cargo selection and autophagosome formation. Given small molecule inhibitors have not been well developed to target LC3, we aim to design and synthesize an LC3 binder and evaluate its activity in the inhibition of autophagy pathway in cancer cells. Methods: The crystal structure of LC3 and p62 complex (PDB: 2ZJD) was used to assist our design of helical sulfonyl-γ-AApeptides to the LC3 interacting region of p62. The peptidomimetics were synthesized on the solid phase and purified by HPLC. We used fluorescent polarization assay to assess the binding affinity of the peptidomimetics to LC3. We then utilized an LC3 HiBiT reporter cell line (U2OS) from Promega, which was engineered to have a fused human LC3-HiBiT with a HaloTag in between to study the effect of the lead LC3 binder on autophagic flux. In addition, confocal microscopy enabled direction visualization of the colocalization of FITC-labeled LC3 binder with LC3 and lysosome, respectively. Cytotoxicity of LC3 binder was evaluated in colorectal cancer cell line HCT116. Results: We designed and synthesized 6 helical sulfonyl-γ-AApeptides (JC1-6) to target the binding interface of LC3 and p62. These peptidomimetic compounds were designed to retain essential LC3 and p62 interactions at the W and L regions and yet have different functional groups on the helical scaffold. Compounds JC1 and JC6 have binding affinity of Kd 280 nM and 150 nM with LC3, respectively. FITC-labelled JC6 was able to penetrate U2OS and HCT116 cells. It had intracytoplasmic colocalization with not only lysosomes but also LC3 aggregates. Direct visualization of intracytoplasmic LC3 aggregates showed that JC6 at 50 µM significantly inhibited the autophagic degradation of LC3 aggregates. This effect was augmented by the presence of 2 µM autophagy activator PP242. Lastly, JC6 demonstrated cytotoxicity with IC50 approximately 50 µM in HCT116 cells bearing baseline autophagy activation compared to lack of cytotoxicity in U2OS cells with no baseline autophagy activity. Conclusion: We designed and synthesized novel helical sulfonyl-γ-AApeptide LC3 binders. With the ability of cellular penetration, they demonstrated inhibition of autophagic flux and preliminary cytotoxicity in cancer cells. Future studies may focus on structural activity relationship and further evaluation of its mechanisms of action in cancer cells. Citation Format: Mentalla Mahmoud, Jianyu Chen, Jianfeng Cai, Hao Xie. Discovery of helical sulfonyl-γ-AApeptides targeting LC3 in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3101.

Molecular Mechanism of Sirtuin 1 Inhibition by Human Immunodeficiency Virus 1 Tat Protein.

Sirtuins are NAD+-dependent protein lysine deacylases implicated in metabolic regulation and aging-related dysfunctions. The nuclear isoform Sirt1 deacetylates histones and transcription factors and contributes, e.g., to brain and immune cell functions. Upon infection by human immunodeficiency virus 1 (HIV1), Sirt1 deacetylates the viral transactivator of transcription (Tat) protein to promote the expression of the viral genome. Tat, in turn, inhibits Sirt1, leading to the T cell hyperactivation associated with HIV infection. Here, we describe the molecular mechanism of Tat-dependent sirtuin inhibition. Using Tat-derived peptides and recombinant Tat protein, we mapped the inhibitory activity to Tat residues 34-59, comprising Tat core and basic regions and including the Sirt1 deacetylation site Lys50. Tat binds to the sirtuin catalytic core and inhibits Sirt1, Sirt2, and Sirt3 with comparable potencies. Biochemical data and crystal structures of sirtuin complexes with Tat peptides reveal that Tat exploits its intrinsically extended basic region for binding to the sirtuin substrate binding cleft through substrate-like β-strand interactions, supported by charge complementarity. Tat Lys50 is positioned in the sirtuin substrate lysine pocket, although binding and inhibition do not require prior acetylation and rely on subtle differences to the binding of regular substrates. Our results provide mechanistic insights into sirtuin regulation by Tat, improving our understanding of physiological sirtuin regulation and the role of this interaction during HIV1 infection.

Integratedin silico–in vitrorational design of oncogenic EGFR-derived specific monoclonal antibody-binding peptide mimotopes

Human epidermal growth factor receptor (EGFR) is strongly associated with malignant proliferation and has been established as an attractive therapeutic target of diverse cancers and used as a significant biomarker for tumor diagnosis. Over the past decades, a variety of monoclonal antibodies (mAbs) have been successfully developed to specifically recognize the third subdomain (TSD) of EGFR extracellular domain. Here, the complex crystal structures of EGFR TSD subdomain with its cognate mAbs were examined and compared systematically, revealing a consistent binding mode shared by these mAbs. The recognition site is located on the [Formula: see text]-sheet surface of TSD ladder architecture, from which several hotspot residues that significantly confer both stability and specificity to the recognition were identified, responsible for about half of the total binding potency of mAbs to TSD subdomain. A number of linear peptide mimotopes were rationally designed to mimic these TSD hotspot residues in different orientations and/or in different head-to-tail manners by using an orthogonal threading-through-strand (OTTS) strategy, which, however, are intrinsically disordered in Free State and thus cannot be maintained in a native hotspot-like conformation. A chemical stapling strategy was employed to constrain the free peptides into a double-stranded conformation by introducing a disulfide bond across two strand arms of the peptide mimotopes. Both empirical scoring and [Formula: see text]fluorescence assay reached an agreement that the stapling can effectively improve the interaction potency of OTTS-designed peptide mimotopes to different mAbs, with binding affinity increase by [Formula: see text]-fold. Conformational analysis revealed that the stapled cyclic peptide mimotopes can spontaneously fold into a double-stranded conformation that well threads through all the hotspot residues on TSD [Formula: see text]-sheet surface and exhibits a consistent binding mode with the TSD hotspot site to mAbs.

Comment on “Crystallographic and theoretical study of the atypical distorted octahedral geometry of the metal chromophore of zinc(II) bis((1R,2R)-1,2-diaminocyclohexane) dinitrate”

We comment on the crystal structure of an enanantipure chiral zinc complex which has been described by Ivanova & Spiteller (2022) erroneously in a centrosymmetric space group with the metal on an inversion center. Subsequent information about thermal motion, octahedral distortion and charge density in their article is highly flawed.

Amplitude expansion of the phase-field crystal model for complex crystal structures

The phase-field crystal (PFC) model describes crystal lattices at diffusive timescales. Its amplitude expansion (APFC) can be applied to the investigation of relatively large systems under some approximations. However, crystal symmetries accessible within the APFC model are limited to basic ones, namely triangular and square in two dimensions, and body-centered cubic and face-centered cubic in three dimensions. In this work, we propose a general, amplitudes-based description of virtually any lattice symmetry. To fully exploit the advantages of this model, featuring slowly varying quantities in bulk and localized significant variations at dislocations and interfaces, we consider formulations suitable for real-space numerical methods supporting adaptive spatial discretization. We explore approaches originally proposed for the PFC model which allow for symmetries beyond basic ones through extended parametrizations. Moreover, we tackle the modeling of non-Bravais lattices by introducing an amplitude expansion for lattices with a basis and further generalizations. We study and discuss the stability of selected, prototypical lattice symmetries. As pivotal examples, we show that the proposed approach allows for a coarse-grained description of the kagome lattice, exotic square arrangements, and the diamond lattice, as bulk crystals and, importantly, hosting dislocations.

Cryo-EM reveals the structure and dynamics of a 723-residue malate synthase G

Determination of sub-100 kDa (kDa) structures by cryo-electron microscopy (EM) is a longstanding but not straightforward goal. Here, we present a 2.9-Å cryo-EM structure of a 723-amino acid apo-form malate synthase G (MSG) from Escherichia coli. The cryo-EM structure of the 82-kDa MSG exhibits the same global folding as structures resolved by crystallography and nuclear magnetic resonance (NMR) spectroscopy, and the crystal and cryo-EM structures are indistinguishable. Analyses of MSG dynamics reveal consistent conformational flexibilities among the three experimental approaches, most notably that the α/β domain exhibits structural heterogeneity. We observed that sidechains of F453, L454, M629, and E630 residues involved in hosting the cofactor acetyl-CoA and substrate rotate differently between the cryo-EM apo-form and complex crystal structures. Our work demonstrates that the cryo-EM technique can be used to determine structures and conformational heterogeneity of sub-100 kDa biomolecules to a quality as high as that obtained from X-ray crystallography and NMR spectroscopy.

Thiourea-Based Tritopic Halogen-Bonding Acceptors.

A series of thiourea-based tritopic receptor molecules were synthesized to be used as building blocks for halogen-bonded assemblies. Here, 16 new receptor molecules were synthesized from two different 2,4,6-trialkyl-1,3,5-tris(bromomethyl)benzene starting materials via tris(isothiocyanatomethyl)benzene intermediates. The alkyl substituents in the benzene ring proved to be important for isothiocyanate group formation instead of competing thiocyanate group. The synthesis route allowed us to synthesize the isothiocyanate intermediates and further the receptor molecules without the typically used and highly toxic thiophosgene. The synthesized receptor molecules were used to study their halogen-bond acceptor properties with diiodotetrafluorobenzene donors by single-crystal X-ray diffraction method. We were able to obtain five new crystal structures of halogen-bonded complexes, in which all receptors showed two to four accepted C-I⋅⋅⋅S halogen bonds. The observed halogen bonds were highly directional and showed large variation in C=S⋅⋅⋅I acceptor angles, indicating flexible acceptor properties of sulfur.

Inverse design of ligands using a deep generative model semi‐supervised by a data‐driven ligand field strength metric

AbstractTransition metal (TM) complexes exhibit diverse structural and electronic properties. The properties of a TM complex can be tuned by modulating the ligand field strength (LFS) inflicted by its ligands. Current quantification of the LFS of a ligand is mainly derived from experimental measurements on a subset of highly symmetrical TM complexes and is limited in ligand scope. Herein, we report a data‐driven method to quantify the LFS of ligands assigned from experimental crystal structures of TM complexes. We first show that the experimental metal–ligand bond lengths of over 4,000 mononuclear Fe, Co, and Mn complexes form bimodal distributions. Using Gaussian fits on the bimodal distributions, each TM complex is assigned a spin state (SS) label. These SS labels can then be used to calculate the LFS of the ligands of the complexes. Using the obtained data‐driven LFS metric, we establish that a semi‐supervised deep generative model, junction tree variational autoencoder (JTVAE), can be employed to predict LFS values. Our model exhibits a mean absolute error (MAE) of 0.047 and root mean squared error of 0.072 on the training set. The model also allows the generation of novel ligands with desirable LFS values.

Structural requirement of RARγ agonism through computational aspects

RARγ is a therapeutic target for many skin diseases and has potential in cancer treatment. In the current study, we put forward a comprehensive structure-activity relationship study of third and fourth generations of RARγ agonists, addressing multiple crystal structures of RARγ complexes and approved drugs. Adapalene and Trifarotene, through hybrid strategies including protein contacts Atlas analysis, molecular docking, dynamics simulations, MM-GBSA, ASM, and pharmacophore modeling. Our result revealed crucial amino acids Arg267, Ser278, Phe288, Phe230, Met272, Leu271, and Leu268 within the RARγ pocket, as well as pharmacophore features such as two hydrophobic groups, two aromatic rings, and negative ionic features, which are essential for the binding of RARγ agonists. Based on this study, the binding mechanism of RARγ agonists was elucidated, which will be helpful for the rational design of new RARγ agonists for skin diseases and cancer treatment. In this study, Schrödinger suite 2021-2 with OPLS_4 force field, Discovery Studio program 3.0, LigandScout 4.3, and PyMOL are utilized in the investigation.

Hirshfeld Atom Refinement of Metal-Organic Complexes: Treatment of Hydrogen Atoms Bonded to Transition Metals.

Hydrogen positions in hydrides play a key role in hydrogen storage materials and high-temperature superconductors. Our recently published study of five crystal structures of transition-metal-bound hydride complexes showed that using aspherical atomic scattering factors for Hirshfeld atom refinement (HAR) resulted in a systematic elongation of metal-hydrogen bonds compared to using spherical scattering factors with the Independent Atom Model (IAM). Even though only standard-resolution X-ray data was used, for the highest-quality data, we obtained excellent agreement between the X-ray and the neutron-derived bond lengths. We present an extended version of this study including 10 crystal structures of metal-organic complexes containing hydrogen atoms bonded to transition-metal atoms for which both X-ray and neutron data are available. The neutron structures were used as a benchmark, and the X-ray structures were refined by applying Hirshfeld atom refinement using various basis sets and DFT functionals in order to investigate the influence of the technical aspects on the length of metal-hydrogen bonds. The result of including relativistic effects in the Hamiltonian and using a cluster of multipoles simulating interactions with a crystal environment during wave function calculations was examined. The effect of the data quality on the final result was also evaluated. The study confirms that a high quality of experimental data is the key factor allowing us to obtain significant improvement in transition metal (TM)-hydrogen bond lengths from HAR in comparison with the IAM. Individual adjustments and better choices of the basis set can improve hydrogen positions. Average differences between TM-H bond lengths obtained with various DFT functionals upon including relativistic effects or between double-ζ and triple-ζ basis sets were not statistically significant. However, if all bonds formed by H atoms were considered, significant differences caused by different refinement strategies were observed. Finally, we examined the refinement of atomic thermal motions. Anisotropic refinement of hydrogen thermal motions with HAR was feasible only in some cases, and isotropically refined hydrogen thermal motions were in similar agreement with neutron values whether obtained with HAR or with the IAM.

Structural basis of main proteases of HCoV-229E bound to inhibitor PF-07304814 and PF-07321332

PF-07321332 and PF-07304814, inhibitors against SARS-CoV-2 developed by Pfizer, exhibit broad-spectrum inhibitory activity against the main protease (Mpro) from various coronaviruses. Structures of PF-07321332 or PF-07304814 in complex with Mpros of various coronaviruses reveal their inhibitory mechanisms against different Mpros. However, the structural information on the lower pathogenic coronavirus Mpro with PF-07321332 or PF-07304814 is currently scarce, which hinders our comprehensive understanding of the inhibitory mechanisms of these two inhibitors. Meanwhile, given that some immunocompromised individuals are still affected by low pathogenic coronaviruses, we determined the structures of lower pathogenic coronavirus HCoV-229E Mpro with PF-07321332 and PF-07304814, respectively, and analyzed and defined in detail the structural basis for the inhibition of HCoV-229E Mpro by both inhibitors. Further, we compared the crystal structures of multiple coronavirus Mpro complexes with PF-07321332 or PF-07304814 to illustrate the differences in the interaction of Mpros, and found that the inhibition mechanism of lower pathogenic coronavirus Mpro was more similar to that of moderately pathogenic coronaviruses. Our structural studies provide new insights into drug development for low pathogenic coronavirus Mpro, and provide theoretical basis for further optimization of both inhibitors to contain potential future coronaviruses.

Dinuclear Zn(II) complexes with Schiff base ligands derived from 4-aminoantipyrine; crystal structure and catalytic activity in the synthesis of tetrazoles

Two new phenolato bridged dinucelar Zn(II) complexes, [Zn2(L1)2(N3)2] (1) and [Zn2(L2)2(N3)2] (2), were synthesized where HL1 and HL2 are tridentate Schiff base ligands obtained from the reaction of 4-aminoantipyrine with 5-bromo-2-hydroxybenzaldehyde and 2-hydroxybenzaldehyde, respectively. The ligands and complexes were characterized by elemental analysis and spectroscopic methods. Crystal structures of complexes 1 and 2 were determined by X-ray analysis which revealed the Zn(II) ions in both of these neutral dinuclear complexes are five coordinated and have distorted square pyramidal geometry. The equatorial plane of this geometry is filled by ONO-donor atoms of the ligands and the axial position is filled by azide co-ligand. Intermolecular interactions in the crystal structure of 1 and 2 were studied by Hirshfeld surface analysis. Due to the presence of azide ligand in the structure of these complexes, they were used as catalysts in the synthesis of 5-phenyl-1H-tetrazole from the reaction of benzonitrile and sodium azide. The results indicated that complexes 1 and 2 are active catalysts for the synthesis of tetrazoles from nitrile and azide cycloaddition reaction.