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1.
Dalton Trans ; 51(24): 9336-9347, 2022 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-35670623

RESUMO

Luminescent metal organic frameworks (LMOFs) are considered to be a type of promising optical sensing material due to their designable and tunable functions, and stable pore structures. Therefore, the preparation of LMOFs has become a research hotspot in recent years. As we know, triazine carboxylic acid ligands are conducive for constructing LMOF materials due to their large π electron conjugated system. In this work, two crystalline materials [Cd3(TCPT)2]·0.5DMF·4H2O (1) and (H3O)[Zn2(TCPT)(µ2-OH)2]·0.5DMF·3H2O (2) were obtained by the reaction of the triazine carboxylic acid ligand 2,4,6-tris(4-carboxyphenoxy)-1,3,5-triazine (H3TCPT), as an extended carboxylate arm, and d10 transition metal salts. Their structures were determined by single crystal X-ray diffraction and characterized by infrared spectroscopy (IR), ultraviolet visible spectroscopy (UV-vis), fluorescence spectroscopy, powder X-ray diffraction (PXRD) and thermogravimetric analysis (TG). The experimental results showed that complexes 1 and 2 show excellent fluorescent emission behavior. Thus, we explored their fluorescence sensing properties. To our delight, the results showed that they both had the ability to sense small organic drug molecules and aromatic amine molecules containing o-phenylenediamine (OPD), m-phenylenediamine (MPD) and p-phenylenediamine (PPD). In general, the practical applications of a MOF material are usually limited because of the relatively harsh synthesis methods. In this aspect, we studied the synthesis method in detail to obtain the optimal reaction conditions for the large-scale synthesis of 1 and 2. The preparation of the two LMOF materials only required about 3 hours of heating time and they could be prepared on a large scale, which is significant for the practical applications of LMOFs.


Assuntos
Estruturas Metalorgânicas , Aminas , Ácidos Carboxílicos , Ligantes , Estruturas Metalorgânicas/química , Modelos Moleculares , Oxigênio , Triazinas , Ácidos Tricarboxílicos
2.
J Mol Graph Model ; 115: 108228, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35667141

RESUMO

Discovering new hit small molecules binding to a specific protein binding site can be a difficult task. In support of existing procedures, a proof of concept methodology has been developed to process fragment flooded X-ray protein structures using the K-means clustering algorithm in order to derive pharmacophore models of the binding site. The novel method includes the implementation of several K-means initialisation methods in serial and parallel versions. Furthermore, required parameter optimisations for two initialisation methods was achieved, which was necessary to determine their validity and performance. A graph theory algorithm was adapted to compare the clustering-derived pharmacophores with X-ray ligand structure-derived pharmacophores to confirm that they mapped to each other. Initial proof of concept method validation was demonstrated using the Androgen Receptor (AR).


Assuntos
Descoberta de Drogas , Proteínas , Algoritmos , Sítios de Ligação , Análise por Conglomerados , Ligantes , Modelos Moleculares , Ligação Proteica
3.
J Mol Biol ; 434(11): 167452, 2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35662453

RESUMO

3D structures of RNAs are the basis for understanding their biological functions. However, experimentally solved RNA 3D structures are very limited. Therefore, many computational methods have been proposed to solve this problem, including our 3dRNA. 3dRNA is an automated template-based method of building RNA 3D structures from sequences and secondary structures by using the smallest secondary elements (SSEs) (http://biophy.hust.edu.cn/new/3dRNA). The first version of 3dRNA simply predicts an assembled structure for a target RNA. Later, it is improved to generate a set of assembled models and a method to further optimize them using experimental or theoretical restraints. In particular, pseudoknot base pairings are treated as restraints to solve the problem of no 3D templates for pseudoknots. Here 3dRNA is further extended to predict the 3D structures of circular RNAs since thousands of circular RNAs have been found recently but no 3D structures of them have been determined up to now. We show that circular RNAs can be divided into four types and two types show similar 3D structures with their linear counterparts while two types very different. We also show that the predicted structures of circular RNAs can bind to their ligands more stable than those of their linear counterparts, consistent with experimental results.


Assuntos
Imageamento Tridimensional , RNA Circular , Software , Algoritmos , Modelos Moleculares , Conformação de Ácido Nucleico , RNA Circular/química
4.
Molecules ; 27(11)2022 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-35684489

RESUMO

The cyclic anhydrides are broadly employed in several fields, such as the chemical, plastic, agrochemical, and pharmaceutical industries. This study describes the chemical reactivity of 4,5-dichlorophthalic anhydride towards several nucleophiles, including thiosemicarbazide and different amines, to produce the carboxylic acid derivatives resulting from anhydride's opening, namely, phthalimide and dicarboxylic acid (1-12) products. Their chemical structures are confirmed by NMR, IR and MS spectra analyses. Density-functional theory (DFT) studies are performed using (DFT/B3LYP) with the 6-311G(d, p) basis sets to recognize different chemical and physical features of the target compounds.


Assuntos
Aminas , Anidridos , Aminas/química , Anidridos/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Teoria Quântica , Semicarbazidas , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman
5.
Molecules ; 27(11)2022 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-35684561

RESUMO

2,4-bis (3,5-dimethyl-1H-pyrazol-1-yl)-6-methoxy-1,3,5-triazine (BPMT) pincer ligand was used to synthesize the new [Zn(BPMT)(NCS)2] (1) and [Zn(BPMT)(Br)2] (2) complexes by a reaction with Zn(NO3)2·6H2O in the presence of either KSCN or KBr, respectively. The structure of complex 1 has been exclusively confirmed using single crystal X-ray diffraction. In this neutral heteroleptic complex, the BPMT is a pincer chelate coordinating the Zn(II) ion via three interactions with the two pyrazole moieties and the s-triazine core. Hence, BPMT is a tridentate NNN-chelate. The coordination environment of Zn(II) is completed by two strong interactions with two terminal SCN- ions via the N-atom. Hence, the Zn(II) is penta-coordinated with a distorted square pyramidal coordination geometry. Hirshfeld analysis indicated the predominance of H…H, H…C and N…H intermolecular interactions. Additionally, the S…H, S…C and S…N contacts are the most significant. The free ligand has no or weak antimicrobial, antioxidant and anticancer activities while the studied Zn(II) complexes showed interesting biological activity. Complex 1 has excellent antibacterial activity against B. subtilis (2.4 µg/mL) and P. vulgaris (4.8 µg/mL) compared to Gentamycin (4.8 µg/mL). Additionally, complex 1 (78.09 ± 4.23 µg/mL) has better antioxidant activity than 2 (365.60 ± 20.89 µg/mL). In addition, complex 1 (43.86 ± 3.12 µg/mL) and 2 (30.23 ± 1.26 µg/mL) have 8 and 12 times the anticancer activity of the free BPMT ligand (372.79 ± 13.64 µg/mL).


Assuntos
Complexos de Coordenação , Compostos Organometálicos , Quelantes/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Cristalografia por Raios X , Íons , Ligantes , Modelos Moleculares , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Triazinas/química , Triazinas/farmacologia , Zinco/química
6.
Sci Signal ; 15(737): eabi7031, 2022 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-35671340

RESUMO

In cell membranes, G protein-coupled receptors (GPCRs) interact with cholesterol, which modulates their assembly, stability, and conformation. Previous studies have shown how cholesterol modulates the structural properties of GPCRs at ambient temperature. Here, we characterized the mechanical, kinetic, and energetic properties of the human ß2-adrenergic receptor (ß2AR) in the presence and absence of the cholesterol analog cholesteryl hemisuccinate (CHS) at room temperature (25°C), at physiological temperature (37°C), and at high temperature (42°C). We found that CHS stabilized various structural regions of ß2AR differentially, which changed nonlinearly with temperature. Thereby, the strongest effects were observed for structural regions that are important for receptor signaling. Moreover, at 37°C, but not at 25° or 42°C, CHS caused ß2AR to increase and stabilize conformational substates to adopt to basal activity. These findings indicate that the nonlinear, temperature-dependent action of CHS in modulating the structural and functional properties of this GPCR is optimized for 37°C.


Assuntos
Colesterol , Colesterol/metabolismo , Humanos , Cinética , Modelos Moleculares , Temperatura
7.
J Mol Model ; 28(7): 195, 2022 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-35727345

RESUMO

A fluorescent probe Pi with the excited-state intramolecular proton transfer (ESIPT) properties was synthesized and used to detect the phosgene in solution and gas phases. However, the detection mechanism of the fluorescent probe needs to be further studied. Herein, the density functional theory (DFT) and time-dependent density functional theory (TD-DFT) methods were adopted to explore the molecular structures and electronic spectra properties of probe and its product Pio after reacting with phosgene. Through analysis for molecular structure parameters and infrared vibrations accompanied with the hydrogen bond of Pi, it is confirmed that the intramolecular hydrogen bond of Pi is enhanced under light excitation, which illustrates the occurrence of ESIPT reaction combined with the scanned potential energy curves. It can be seen from the simulated spectra that Pi shows double fluorescence through ESIPT process, while the fluorescent product Pio exhibits the single fluorescence due to the disappearance of intramolecular hydrogen bond. Through the study on the structure and optical properties of Pi and Pio, it can be helpful to deeply understand the intrinsic mechanism of the detection of phosgene by the Pi molecule probe, which also supplies a reference to the further study about the fluorescence probe.


Assuntos
Fosgênio , Prótons , Corantes Fluorescentes/química , Modelos Moleculares , Teoria Quântica
8.
Chem Rev ; 122(12): 10579-10580, 2022 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-35730197
9.
J Chem Phys ; 156(23): 234105, 2022 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-35732531

RESUMO

Mechanical properties of nucleic acids play an important role in many biological processes that often involve physical deformations of these molecules. At sufficiently long length scales (say, above ∼20-30 base pairs), the mechanics of DNA and RNA double helices is described by a homogeneous Twistable Wormlike Chain (TWLC), a semiflexible polymer model characterized by twist and bending stiffnesses. At shorter scales, this model breaks down for two reasons: the elastic properties become sequence-dependent and the mechanical deformations at distal sites get coupled. We discuss in this paper the origin of the latter effect using the framework of a non-local Twistable Wormlike Chain (nlTWLC). We show, by comparing all-atom simulations data for DNA and RNA double helices, that the non-local couplings are of very similar nature in these two molecules: couplings between distal sites are strong for tilt and twist degrees of freedom and weak for roll. We introduce and analyze a simple double-stranded polymer model that clarifies the origin of this universal distal couplings behavior. In this model, referred to as the ladder model, a nlTWLC description emerges from the coarsening of local (atomic) degrees of freedom into angular variables that describe the twist and bending of the molecule. Different from its local counterpart, the nlTWLC is characterized by a length-scale-dependent elasticity. Our analysis predicts that nucleic acids are mechanically softer at the scale of a few base pairs and are asymptotically stiffer at longer length scales, a behavior that matches experimental data.


Assuntos
Ácidos Nucleicos , DNA , Elasticidade , Modelos Moleculares , Conformação de Ácido Nucleico , Polímeros , RNA
10.
Cell Rep ; 39(10): 110918, 2022 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-35675778

RESUMO

The proteasome holoenzyme regulates the cellular proteome via degrading most proteins. In its 19-subunit regulatory particle (RP), a heterohexameric ATPase enables protein degradation by injecting protein substrates into the core peptidase. RP assembly utilizes "checkpoints," where multiple dedicated chaperones bind to specific ATPase subunits and control the addition of other subunits. Here, we find that the RP assembly checkpoint relies on two common features of the chaperones. Individual chaperones can distinguish an RP, in which their cognate ATPase persists in the ATP-bound state. Chaperones then together modulate ATPase activity to facilitate RP subunit rearrangements for switching to an active, substrate-processing state in the resulting proteasome holoenzyme. Thus, chaperones may sense ATP binding and hydrolysis as a readout for the quality of the RP complex to generate a functional proteasome holoenzyme. Our findings provide a basis to potentially exploit the assembly checkpoints in situations with known deregulation of proteasomal ATPase chaperones.


Assuntos
Complexo de Endopeptidases do Proteassoma , Proteínas de Saccharomyces cerevisiae , Adenosina Trifosfatases/metabolismo , Trifosfato de Adenosina , Holoenzimas/metabolismo , Modelos Moleculares , Chaperonas Moleculares/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo
11.
Science ; 376(6598): eabm9798, 2022 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-35679425

RESUMO

INTRODUCTION In eukaryotic cells, the selective bidirectional transport of macromolecules between the nucleus and cytoplasm occurs through the nuclear pore complex (NPC). Embedded in nuclear envelope pores, the ~110-MDa human NPC is an ~1200-Å-wide and ~750-Å-tall assembly of ~1000 proteins, collectively termed nucleoporins. Because of the NPC's eightfold rotational symmetry along the nucleocytoplasmic axis, each of the ~34 different nucleoporins occurs in multiples of eight. Architecturally, the NPC's symmetric core is composed of an inner ring encircling the central transport channel and two outer rings anchored on both sides of the nuclear envelope. Because of its central role in the flow of genetic information from DNA to RNA to protein, the NPC is commonly targeted in viral infections and its nucleoporin constituents are associated with a plethora of diseases. RATIONALE Although the arrangement of most scaffold nucleoporins in the NPC's symmetric core was determined by quantitative docking of crystal structures into cryo-electron tomographic (cryo-ET) maps of intact NPCs, the topology and molecular details of their cohesion by multivalent linker nucleoporins have remained elusive. Recently, in situ cryo-ET reconstructions of NPCs from various species have indicated that the NPC's inner ring is capable of reversible constriction and dilation in response to variations in nuclear envelope membrane tension, thereby modulating the diameter of the central transport channel by ~200 Å. We combined biochemical reconstitution, high-resolution crystal and single-particle cryo-electron microscopy (cryo-EM) structure determination, docking into cryo-ET maps, and physiological validation to elucidate the molecular architecture of the linker-scaffold interaction network that not only is essential for the NPC's integrity but also confers the plasticity and robustness necessary to allow and withstand such large-scale conformational changes. RESULTS By biochemically mapping scaffold-binding regions of all fungal and human linker nucleoporins and determining crystal and single-particle cryo-EM structures of linker-scaffold complexes, we completed the characterization of the biochemically tractable linker-scaffold network and established its evolutionary conservation, despite considerable sequence divergence. We determined a series of crystal and single-particle cryo-EM structures of the intact Nup188 and Nup192 scaffold hubs bound to their Nic96, Nup145N, and Nup53 linker nucleoporin binding regions, revealing that both proteins form distinct question mark-shaped keystones of two evolutionarily conserved hetero­octameric inner ring complexes. Linkers bind to scaffold surface pockets through short defined motifs, with flanking regions commonly forming additional disperse interactions that reinforce the binding. Using a structure­guided functional analysis in Saccharomyces cerevisiae, we confirmed the robustness of linker­scaffold interactions and established the physiological relevance of our biochemical and structural findings. The near-atomic composite structures resulting from quantitative docking of experimental structures into human and S. cerevisiae cryo-ET maps of constricted and dilated NPCs structurally disambiguated the positioning of the Nup188 and Nup192 hubs in the intact fungal and human NPC and revealed the topology of the linker-scaffold network. The linker-scaffold gives rise to eight relatively rigid inner ring spokes that are flexibly interconnected to allow for the formation of lateral channels. Unexpectedly, we uncovered that linker­scaffold interactions play an opposing role in the outer rings by forming tight cross-link staples between the eight nuclear and cytoplasmic outer ring spokes, thereby limiting the dilatory movements to the inner ring. CONCLUSION We have substantially advanced the structural and biochemical characterization of the symmetric core of the S. cerevisiae and human NPCs and determined near-atomic composite structures. The composite structures uncover the molecular mechanism by which the evolutionarily conserved linker­scaffold establishes the NPC's integrity while simultaneously allowing for the observed plasticity of the central transport channel. The composite structures are roadmaps for the mechanistic dissection of NPC assembly and disassembly, the etiology of NPC­associated diseases, the role of NPC dilation in nucleocytoplasmic transport of soluble and integral membrane protein cargos, and the anchoring of asymmetric nucleoporins. [Figure: see text].


Assuntos
Complexo de Proteínas Formadoras de Poros Nucleares , Poro Nuclear , Proteínas de Saccharomyces cerevisiae , Microscopia Crioeletrônica , Humanos , Modelos Moleculares , Poro Nuclear/química , Complexo de Proteínas Formadoras de Poros Nucleares/química , Conformação Proteica , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/química
12.
ChemistryOpen ; 11(6): e202200026, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35701378

RESUMO

We review here the use of container molecules known as cavitands for performing organic reactions in water. Central to these endeavors are binding forces found in water, and among the strongest of these is the hydrophobic effect. We describe how the hydrophobic effect can be used to drive organic molecule guests into the confined space of cavitand hosts. Other forces participating in guest binding include cation-π interactions, chalcogen bonding and even hydrogen bonding to water involved in the host structure. The reactions of guests take advantage of their contortions in the limited space of the cavitands which enhance macrocyclic and site-selective processes. The cavitands are applied to the removal of organic pollutants from water and to the separation of isomeric guests. Progress is described on maneuvering the containers from stoichiometric participation to roles as catalysts.


Assuntos
Éteres Cíclicos , Água , Calixarenos , Éteres Cíclicos/química , Modelos Moleculares , Fenilalanina/análogos & derivados , Resorcinóis , Água/química
13.
Acta Crystallogr B Struct Sci Cryst Eng Mater ; 78(Pt 3 Pt 1): 397-415, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35695114

RESUMO

The Hirshfeld atom-based X-ray constrained wavefunction fitting (HA-XCW) procedure is tested for its reproducibility, and the information content of the fitted wavefunction is critically assessed. Fourteen different α-oxalic acid dihydrate data sets are used for this purpose, and the first joint fitting to 12 of these data sets is reported. There are systematic features in the electron density obtained from all data sets which agree with higher level benchmark calculations, but there are also many other strong systematic features which disagree with the reference calculations, most notably those associated with the electron density near the nuclei. To enhance reproducibility, three new protocols are described and tested to address the halting problem of XCW fitting, namely: an empirical power-function method, which is useful for estimating the accuracy of the structure factor uncertainties; an asymptotic extrapolation method based on ideas from density functional theory; and a `conservative method' whereby the smallest value of the regularization parameter is chosen from a series of data sets, or subsets.


Assuntos
Elétrons , Ácido Oxálico , Cristalografia por Raios X , Modelos Moleculares , Reprodutibilidade dos Testes , Raios X
14.
Acta Crystallogr D Struct Biol ; 78(Pt 6): 709-715, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35647918

RESUMO

The ease with which racemic mixtures crystallize compared with the equivalent chiral systems is routinely taken advantage of to produce crystals of small molecules. However, biological macromolecules such as DNA and proteins are naturally chiral, and thus the limited range of chiral space groups available hampers the crystallization of such molecules. Inspiring work over the past 15 years has shown that racemic mixtures of proteins, which were made possible by impressive advances in protein chemical synthesis, can indeed improve the success rate of protein crystallization experiments. More recently, the racemic crystallization approach was extended to include nucleic acids as a possible aid in the determination of enantiopure DNA crystal structures. Here, findings are reported that suggest that the benefits may extend beyond this. Two racemic crystal structures of the DNA sequence d(CCCGGG) are described which were found to fold into A-form DNA. This form differs from the Z-form DNA conformation adopted by the chiral equivalent in the solid state, suggesting that the use of racemates may also favour the emergence of new conformations. Importantly, the racemic mixture forms interactions in the solid state that differ from the chiral equivalent (including the formation of racemic pseudo-helices), suggesting that the use of racemic DNA mixtures could provide new possibilities for the design of precise self-assembled nanomaterials and nanostructures.


Assuntos
DNA Forma A , Cristalização , DNA/química , Modelos Moleculares , Proteínas , Estereoisomerismo
15.
Acta Crystallogr D Struct Biol ; 78(Pt 6): 770-778, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35647923

RESUMO

Hen egg-white lysozyme (HEWL) is an enzymatic protein with two acidic amino acids, Glu35 and Asp52, in its active site. Glu35 acts as a proton donor to the substrate and Asp52 interacts with the positively charged substrate, suggesting different protonation states of these residues. However, neutron crystallographic studies thus far have not provided a consistent picture of the protonation states of these residues. Only one study succeeded in observing the active protonation states of Glu35 and Asp52 in the triclinic crystal system. However, their active states in the most widely studied tetragonal crystal system are still unknown. The application of the D/H contrast technique in neutron crystallography improves the ability to locate exchangeable D/H atoms in proteins. In the present study, D2O and H2O solvent crystals were prepared. Each neutron data set was collected for only five days by combining a time-of-flight diffractometer (iBIX) and the spallation neutron source at the Japan Proton Accelerator Research Complex. The D/H contrast map provided better visualization of the D/H atoms in HEWL than the conventional neutron scattering length density map. The neutron D/H contrast map demonstrated the alternative protonation of the OE1 and OE2 atoms in the carboxyl group of Glu35. This alternative protonation occurs in the absence of a substrate, where high selectivity of the protonation site does not occur. In this case, only the OE1-HE1 bond attacks the substrate in an equilibrium between OE1-HE1 and OE2-HE2, or the H+ ion of the OE2-HE2 bond moves to the OE1 atom just before or after substrate binding to initiate the catalytic reaction. In contrast, the carboxyl group of Asp52 is not protonated. Protonation of the carboxyl group was not observed for other Asp and Glu residues. These results are consistent with results from NMR spectroscopy and explain the protonation states at the active site in the apo form of HEWL.


Assuntos
Muramidase , Prótons , Cristalografia , Modelos Moleculares , Muramidase/química , Nêutrons
16.
Nat Commun ; 13(1): 3193, 2022 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-35680862

RESUMO

Efficient and accurate DNA synthesis is enabled by DNA polymerase fidelity checkpoints that promote insertion of the right instead of wrong nucleotide. Erroneous X-family polymerase (pol) λ nucleotide insertion leads to genomic instability in double strand break and base-excision repair. Here, time-lapse crystallography captures intermediate catalytic states of pol λ undergoing right and wrong natural nucleotide insertion. The revealed nucleotide sensing mechanism responds to base pair geometry through active site deformation to regulate global polymerase-substrate complex alignment in support of distinct optimal (right) or suboptimal (wrong) reaction pathways. An induced fit during wrong but not right insertion, and associated metal, substrate, side chain and pyrophosphate reaction dynamics modulated nucleotide insertion. A third active site metal hastened right but not wrong insertion and was not essential for DNA synthesis. The previously hidden fidelity checkpoints uncovered reveal fundamental strategies of polymerase DNA repair synthesis in genomic instability.


Assuntos
DNA Polimerase beta , Nucleotídeos , DNA/metabolismo , DNA Polimerase beta/genética , DNA Polimerase beta/metabolismo , Instabilidade Genômica , Humanos , Cinética , Modelos Moleculares , Nucleotídeos/metabolismo
17.
J Org Chem ; 87(12): 7875-7883, 2022 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-35653132

RESUMO

Imidazole-based compounds are widely found in natural products, synthetic molecules, and biomolecules. Noncovalent interactions between the imidazole ring and other functional groups play an important role in determining the function of diverse molecules. However, there is a limited understanding of the underlying noncovalent interactions between imidazoles and aromatic systems. In this work, we report physical-organic chemistry studies on 2-(2,6-diarylphenyl)-1H-imidazoles and their protonated forms to investigate the noncovalent interactions between the central imidazole ring and two flanking aromatic rings possessing substituents at the para/meta position. Hammett analysis revealed that pKa values and proton affinities correlate well with Hammett σ values of para-substituents at the flanking rings. Additional quantitative Kohn-Sham molecular orbital and energy decomposition analyses reveal that through-space π-π interactions and NH-π interactions contribute to the intramolecular stabilization of the imidazolium cation. The results are important because they clearly demonstrate that the imidazolium cation forms energetically favorable noncovalent interactions with aromatic rings via the through-space effect, a knowledge that can be used in rational drug and catalyst design.


Assuntos
Imidazóis , Cátions/química , Imidazóis/química , Modelos Moleculares
18.
Front Immunol ; 13: 884132, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35720356

RESUMO

Single-domain antibodies (sdAbs) are a promising class of biotherapeutics with unique structural traits within their paratope region. The distribution of canonical conformations explored by their complementarity determining region (CDR) loops differs to some extent from conventional two-chain Fv fragments of monoclonal antibodies (mAbs). In this study, we explored in detail the canonical structures of sdAb CDR-H1 and CDR-H2 loops and compared those with mAbs from the IGHV3 and IGHV1 gene families. We surveyed the antibody structures catalogued in SAbDab and clustered the CDR canonical loops in Cartesian space. While most of the sdAb clusters were sub-populations of previously defined canonical Fv conformations of CDR-H1 and CDR-H2, our stricter clustering approach defined narrower clusters in sequence-space. Meticulous visual inspection of sub-populations allowed a clearer understanding of sequence-structure relationships. The packing densities within structural pockets contacted by CDR-H1 and CDR-H2 canonical conformations were analyzed on the premise that these pockets cannot be left vacant as they would leave exposed supportive hydrophobic residues. The fine resolution of the canonical clusters defined here revealed unique signatures within these pockets, including distinct structural complementarities between CDR-H1 and CDR-H2 canonical clusters, which could not be perceived with the previous coarser clusters. We highlight examples where a single residue change in CDR-H1 sequence is sufficient to induce a dramatic population shift in CDR-H2 conformation. This suggests that preferences in combining CDR-H1 and CDR-H2 emerged naturally during antibody evolution, leading to preferred sets of conserved amino acids at key positions in the framework as well as within the CDR loops. We outline a game of musical chairs that is necessary to maintain the integrity of the antibody structures that arose during evolution. Our study also provides refined CDR-H1 and CDR-H2 structural templates for sdAb homology modeling that could be leveraged for improved antibody design.


Assuntos
Anticorpos de Domínio Único , Anticorpos Monoclonais , Regiões Determinantes de Complementaridade/química , Modelos Moleculares , Conformação Proteica
19.
Bioorg Chem ; 126: 105880, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35649315

RESUMO

The [(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) analogs were reported to be a kind of promising lead compounds as nonnucleoside HIV-1 reverse transcriptase inhibitors. In this work, a series of novel sulfinyl-substituted analogs were designed by structure-based design strategy with the purpose of improving the activity of HEPT, followed by evaluating their anti-HIV-1 activity in MT-4 cells. Most of the final compounds had moderate to strong activity against wild-type HIV-1 strain (IIIB) with EC50 values in the range of 0.21-1.91 µM, which were around 4 âˆ¼ 32-fold better than the reference compound HEPT. Some of them showed higher sensitivity toward clinically relevant mutant L100I and E138K viruses than NVP. Selected compounds were further evaluated for their activity against wild-type reverse transcriptase (RT), and most of them exhibited nanomolar activity, suggesting a good correlation with the cell-based activity. The compounds 11h, 11l, and 11ab displayed the best anti-HIV-1 activity against wild-type HIV-1 strain (EC50 = 0.280, 0.209, and 0.290 µM) and nanomolar activity against mutant strains (L100I and E138K), superior to HEPT and NVP. Molecular modeling studies were also performed to elucidate the biological activity, providing a structural insight for follow-up research on HEPT optimization.


Assuntos
Fármacos Anti-HIV , HIV-1 , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV , Modelos Moleculares , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade , Timina/farmacologia
20.
Comput Biol Med ; 146: 105640, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35598354

RESUMO

Thrombi (blood clots) form in blood vessels in thromboembolic disorders, which are among the main reasons for death in the world. A novel approach is presented to predict thrombin inhibitory activities ((log(103/Ki) (nM)) of some classes of non-peptidic thrombin inhibitors. The largest reported data set of log(103/Ki) for 260 thrombin inhibitors are used to derive and test the new model where it can be easily applied through a computer code. The new model is derived and tested based on 201 and 59 experimental data, respectively, where its reliability is established by external and internal validations. The reliability of the novel correlation is compared with the complex 3D-QSAR method CoMSIA based on donor hydrogen bond, electrostatic interactions, steric occupancy, local hydrophobicity, and acceptor hydrogen bond fields. The values of correlation coefficient (R2), and root mean squared error (RMSE) for 138/34 data of training/test sets, where the predicted results of complex CoMSIA calculations were available, are 0.9173/0.6010 (R2), and 0.2503/0.4911 (RMSE) as well as 0.8753/0.3888 (R2), and 0.3287/0.6358 (RMSE) for the new and CoMSIA models, respectively. Further statistical parameters also confirm high reliability, precision, accuracy, and the goodness-of-fit of the simple model.


Assuntos
Relação Quantitativa Estrutura-Atividade , Trombina , Modelos Moleculares , Estrutura Molecular , Reprodutibilidade dos Testes
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