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1.
Chem Pharm Bull (Tokyo) ; 72(6): 540-546, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38866475

RESUMO

Three neo-clerodane diterpenoids, including two new tinocordifoliols A (1) and B (2) and one known tinopanoid R (3), were isolated from the ethyl acetate-soluble fraction of the 70% ethanol extract of Tinospora cordifolia stems. The structures were elucidated by various spectroscopic methods, including one dimensional (1D) and 2D-NMR, high resolution-electrospray ionization (HR-ESI)-MS, and electronic circular dichroism (ECD) data. The T. cordifolia extract and all isolated compounds 1-3 possessed arginase I inhibitory activities. Among them, 3 exhibited moderate competitive inhibition of human arginase I (IC50 = 61.9 µM). Furthermore, docking studies revealed that the presence of a ß-substituted furan in 3 may play a key role in the arginase I inhibitory activities.


Assuntos
Arginase , Diterpenos Clerodânicos , Inibidores Enzimáticos , Simulação de Acoplamento Molecular , Caules de Planta , Tinospora , Tinospora/química , Arginase/antagonistas & inibidores , Arginase/metabolismo , Diterpenos Clerodânicos/farmacologia , Diterpenos Clerodânicos/química , Diterpenos Clerodânicos/isolamento & purificação , Humanos , Caules de Planta/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/isolamento & purificação , Relação Estrutura-Atividade , Estrutura Molecular , Conformação Molecular , Relação Dose-Resposta a Droga
2.
Bioinformatics ; 40(6)2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38837333

RESUMO

MOTIVATION: Cryo-electron microscopy (cryo-EM) is a powerful technique for studying macromolecules and holds the potential for identifying kinetically preferred transition sequences between conformational states. Typically, these sequences are explored within two-dimensional energy landscapes. However, due to the complexity of biomolecules, representing conformational changes in two dimensions can be challenging. Recent advancements in reconstruction models have successfully extracted structural heterogeneity from cryo-EM images using higher-dimension latent space. Nonetheless, creating high-dimensional conformational landscapes in the latent space and then searching for preferred paths continues to be a formidable task. RESULTS: This study introduces an innovative framework for identifying preferred trajectories within high-dimensional conformational landscapes. Our method encompasses the search for the minimum energy path in the graph, where edge weights are determined based on the energy estimation at each node using local density. The effectiveness of this approach is demonstrated by identifying accurate transition states in both synthetic and real-world datasets featuring continuous conformational changes. AVAILABILITY AND IMPLEMENTATION: The CLEAPA package is available at https://github.com/tengyulin/energy_aware_pathfinding/.


Assuntos
Algoritmos , Microscopia Crioeletrônica , Software , Microscopia Crioeletrônica/métodos , Conformação Molecular , Conformação Proteica
3.
Molecules ; 29(11)2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38893334

RESUMO

Thiazolin-4-ones and their derivatives represent important heterocyclic scaffolds with various applications in medicinal chemistry. For that reason, the synthesis of two 5-substituted thiazolidin-4-one derivatives was performed. Their structure assignment was conducted by NMR experiments (2D-COSY, 2D-NOESY, 2D-HSQC and 2D-HMBC) and conformational analysis was conducted through Density Functional Theory calculations and 2D-NOESY. Conformational analysis showed that these two molecules adopt exo conformation. Their global minimum structures have two double bonds (C=N, C=C) in Z conformation and the third double (C=N) in E. Our DFT results are in agreement with the 2D-NMR measurements. Furthermore, the reaction isomerization paths were studied via DFT to check the stability of the conformers. Finally, some potential targets were found through the SwissADME platform and docking experiments were performed. Both compounds bind strongly to five macromolecules (triazoloquinazolines, mglur3, Jak3, Danio rerio HDAC6 CD2, acetylcholinesterase) and via SwissADME it was found that these two molecules obey Lipinski's Rule of Five.


Assuntos
Conformação Molecular , Simulação de Acoplamento Molecular , Tiazolidinas , Tiazolidinas/química , Tiazolidinas/síntese química , Isomerismo , Animais , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Peixe-Zebra , Espectroscopia de Ressonância Magnética , Janus Quinase 3/antagonistas & inibidores , Janus Quinase 3/metabolismo , Janus Quinase 3/química , Estrutura Molecular
4.
J Org Chem ; 89(12): 9135-9138, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38860861

RESUMO

Cyclolithistide A is a peptide lactone isolated from marine lithistid sponges. Its entire structure, including absolute configurations, has been reported except the relative and absolute configurations of its characteristic residue, 4-chloroisoleucine (4-CIle). We synthesized four isomers of 4-CIle from furfural-derived N-Boc imine and propionaldehyde. Analysis of the acid hydrolysate of cyclolithistide A and the synthetic samples of 4-CIle after derivatization with l- and d-FDAA permitted us to propose the absolute configuration of the 4-chloroisoleucine residue in cyclolithistide A as 2S,3R,4R.


Assuntos
Lactonas , Poríferos , Poríferos/química , Animais , Lactonas/química , Antifúngicos/química , Antifúngicos/farmacologia , Estereoisomerismo , Peptídeos Cíclicos/química , Conformação Molecular , Estrutura Molecular
5.
J Chem Inf Model ; 64(11): 4542-4552, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38776465

RESUMO

Identification of all of the influential conformers of biomolecules is a crucial step in many tasks of computational biochemistry. Specifically, molecular docking, a key component of in silico drug development, requires a comprehensive set of conformations for potential candidates in order to generate the optimal ligand-receptor poses and, ultimately, find the best drug candidates. However, the presence of flexible cycles in a molecule complicates the initial search for conformers since exhaustive sampling algorithms via torsional random and systematic searches become very inefficient. The devised inverse-kinematics-based Monte Carlo with refinement (MCR) algorithm identifies independently rotatable dihedral angles in (poly)cyclic molecules and uses them to perform global conformational sampling, outperforming popular alternatives (MacroModel, CREST, and RDKit) in terms of speed and diversity of the resulting conformer ensembles. Moreover, MCR quickly and accurately recovers naturally occurring macrocycle conformations for most of the considered molecules.


Assuntos
Algoritmos , Conformação Molecular , Simulação de Acoplamento Molecular , Método de Monte Carlo , Fenômenos Biomecânicos , Preparações Farmacêuticas/química , Ligantes
6.
Chem Pharm Bull (Tokyo) ; 72(5): 475-479, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38749722

RESUMO

Heterologous expression of natural compound biosynthetic gene clusters (BGCs) is a robust approach for not only revealing the biosynthetic mechanisms leading to the compounds, but also for discovering new products from uncharacterized BGCs. We established a heterologous expression technique applicable to huge biosynthetic gene clusters for generating large molecular secondary metabolites such as type-I polyketides. As an example, we targeted concanamycin BGC from Streptomyces neyagawaensis IFO13477 (the cluster size of 99 kbp), and obtained a bacterial artificial chromosome (BAC) clone with an insert size of 211 kbp that contains the entire concanamycin BGC. Interestingly, heterologous expression for this BAC clone resulted in two additional aromatic polyketides, ent-gephyromycin, and a new compound designated as JBIR-157, together with the expected concanamycin. Bioinformatic and biochemical analyses revealed that a cryptic biosynthetic gene cluster in this BAC clone was responsible for the production of these type-II polyketide synthases (PKS) compounds. Here, we describe the production, isolation, and structure elucidation of JBIR-157, determined primarily by a series of NMR spectral analyses.


Assuntos
Família Multigênica , Policetídeos , Streptomyces , Policetídeos/química , Policetídeos/metabolismo , Policetídeos/isolamento & purificação , Streptomyces/genética , Streptomyces/metabolismo , Streptomyces/química , Estrutura Molecular , Policetídeo Sintases/genética , Policetídeo Sintases/metabolismo , Conformação Molecular
7.
J Biomol Struct Dyn ; 42(10): 5053-5071, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38764131

RESUMO

The synthesis of two new hexahydroisoquinoline-4-carbonitrile derivatives (3a and 3b) is reported along with spectroscopic data and their crystal structures. In compound 3a, the intramolecular O-H···O hydrogen bond constraints the acetyl and hydroxyl groups to be syn. In the crystal, inversion dimers are generated by C-H···O hydrogen bonds and are connected into layers parallel to (10-1) by additional C-H···O hydrogen bonds. The layers are stacked with Cl···S contacts 0.17 Å less than the sum of the respective van der Waals radii. The conformation of the compound 3b is partially determined by the intramolecular O-H···O hydrogen bond. A puckering analysis of the tetrahydroisoquinoline unit was performed. In the crystal, O-H···O and C-H···O hydrogen bonds together with C-H···π(ring) interactions form layers parallel to (01-1) which pack with normal van der Waals interactions. To understand the binding efficiency and stability of the title molecules, molecular docking, and 100 ns dynamic simulation analyses were performed with CDK5A1. To rationalize their structure-activity relationship(s), a DFT study at the B3LYP/6-311++G** theoretical level was also done. The 3D Hirshfled surfaces were also taken to investigate the crystal packings of both compounds. In addition, their ADMET properties were explored.Communicated by Ramaswamy H. Sarma.


Assuntos
Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Cristalografia por Raios X , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/química , Quinases Ciclina-Dependentes/metabolismo , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/farmacologia , Conformação Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Modelos Moleculares , Nitrilas/química , Simulação de Dinâmica Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Humanos
8.
Phytochemistry ; 223: 114138, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38762154

RESUMO

Croton laui (Euphorbiaceae) is a traditional medicinal plant used by the Li ethnic group in China to treat headaches, stomachaches, and diphtheria. To understand the pharmacological basis of its medicinal use, an extensive investigation of the ethanolic extract of the bark of C. laui was performed. After repeated chromatography, twenty-four undescribed labdane-type diterpenoids, lauinoids A-X (1-24), and five known analogs (25-29) were isolated. Their structures and absolute configurations were established using a combination of spectroscopic analyses, electronic circular dichroism, nuclear magnetic resonance calculations, and single-crystal X-ray diffraction. Among them, compounds 1-3 exhibited an 11(12 â†’ 13)-abeo-16-nor-labdane skeleton, which originated putatively from 9 through a plausible pathway that involves a semipinacol rearrangement process. Compounds 11 and 12 belong to the rare class of 14,15-dinor-labdane diterpenoids. Compounds 18 and 28 exhibited substantial inhibitory effects by suppressing lipopolysaccharide-induced NO production in RAW 264.7 macrophages, with IC50 values of 3.37 ± 0.23 and 5.82 ± 0.28 µM, respectively. This study has greatly expanded the chemical diversity of labdane diterpenoids from C. laui and will guide future research on this ethnomedicinal plant.


Assuntos
Anti-Inflamatórios , Croton , Diterpenos , Diterpenos/farmacologia , Diterpenos/química , Diterpenos/isolamento & purificação , Croton/química , Camundongos , Animais , Células RAW 264.7 , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Estrutura Molecular , Relação Estrutura-Atividade , Óxido Nítrico/biossíntese , Óxido Nítrico/antagonistas & inibidores , Conformação Molecular , Relação Dose-Resposta a Droga
9.
Spectrochim Acta A Mol Biomol Spectrosc ; 316: 124346, 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-38692105

RESUMO

Considering the health relevance of Chagas' disease, recent research efforts have focused on developing more efficient drug delivery systems containing nifurtimox (NFX). This paper comprehensively investigates NFX through conformational analysis and spectroscopic characterization. Using a conformer-rotamer ensemble sampling tool (CREST-xtb), five distinct conformers of NFX were sampled within a 3.0 kcal mol-1 relative energy window. Subsequently, such structures were used as inputs for geometry optimization by density functional theory (DFT) at B3LYP-def2-TZVP level of theory. Notably, harmonic vibrational frequencies were calculated to establish an in-depth comparison with experimental results and existing literature for the NFX or similar molecules and functional groups, thereby achieving a widely reasoned assignment of the mid-infrared band absorptions for the first time. Moreover, UV-VIS spectra of NFX were obtained in several solvents, enabling the determination of the molar absorptivity coefficient for the two electronic transitions observed for NFX. Among the aprotic solvents, a bathochromic effect was observed in the function of the dielectric constants. Furthermore, a hypochromic effect was observed when the drug was dissolved in protic solvents. These findings offer crucial support for new drug delivery systems containing NFX while demonstrating the potential of spectrophotometric studies in establishing quality control assays for NFX drug products.


Assuntos
Doença de Chagas , Conformação Molecular , Nifurtimox , Doença de Chagas/tratamento farmacológico , Nifurtimox/química , Espectrofotometria Ultravioleta , Tripanossomicidas/química , Modelos Moleculares , Teoria da Densidade Funcional , Trypanosoma cruzi/efeitos dos fármacos , Solventes/química
10.
Spectrochim Acta A Mol Biomol Spectrosc ; 316: 124377, 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-38701580

RESUMO

Tryptophan (Trp) residue provides characteristic vibrational markers to the middle wavenumber spectral region of the Raman spectra recorded from peptides and proteins. In this report, we were particularly interested in eight Trp Raman markers, referred to as Wi (i = 1,…,8). All responsible for pronounced Raman lines, these markers originate from indole moiety, a bicyclic conjugated segment involved in the Trp structure. Numerous investigations have previously attempted to relate the variations observed in the spectral features of these markers to the environmental changes of Trp residues. To emphasize the most important points we can mention (i) the variations in the Raman profile of W4 (∼1360 cm-1) and W5 (∼1340 cm-1), frequently observed as a doublet with variable intensity ratio. These two markers were thought to result from a Fermi-resonance effect between certain planar and nonplanar modes; (ii) the changes observed in the wavenumbers and relative intensities of W4, W7 (∼880 cm-1) and W8 (∼760 cm-1) were supposed to be related to the accessibility of Trp to surrounding water molecules; and (iii) the wavenumber fluctuations of W3 (∼1550 cm-1), taken as a Trp side chain orientational marker. However, some ambiguities still exist regarding the interpretation of these markers, needing further clarification. Herein, upon a joint experimental and theoretical analysis based on a multiconformational approach, attention was paid to the relationships between structural and vibrational features of three indole-containing compounds with increasing structural complexity, i.e., skatole (3-methylindole), tryptophan, and tripeptide Gly-Trp-Gly. This study clearly shows that the existing assignments given to certain Trp Raman markers should be reconsidered, especially those based on the Fermi-resonance origin of W4-W5 (∼1360-1340 cm-1) doublet, as well as the purely environmental dependence of W7 and W8 markers.


Assuntos
Análise Espectral Raman , Triptofano , Vibração , Triptofano/química , Triptofano/análise , Análise Espectral Raman/métodos , Conformação Molecular , Indóis/química
11.
J Chem Phys ; 160(17)2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38748024

RESUMO

Chromones are a class of naturally occurring compounds, renowned for their diverse biological activities with significant relevance in medicine and biochemistry. This study marks the first analysis of rotational spectra of both the chromone monomer and its monohydrate through Fourier transform microwave spectroscopy. The observation of nine mono-substituted 13C isotopologues facilitated a semi-experimental determination of the equilibrium structure of the chromone monomer. In the case of chromone monohydrate, two distinct isomers were identified, each characterized by a combination of O-H⋯O and C-H⋯O hydrogen bonds involving the chromone's carbonyl group. This study further delved into intermolecular non-covalent interactions, employing different theoretical approaches. The relative population ratio of the two identified isomers was estimated to be about 2:1 within the supersonic jet.


Assuntos
Cromonas , Cromonas/química , Ligação de Hidrogênio , Conformação Molecular , Análise Espectral/métodos , Micro-Ondas , Estrutura Molecular
12.
Anal Chem ; 96(23): 9390-9398, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38812282

RESUMO

Ion mobility mass spectrometry (IM-MS) measures the mass, size, and shape of ions in the same experiment, and structural information is provided via collision cross-section (CCS) values. The majority of commercially available IM-MS instrumentation relies on the use of CCS calibrants, and here, we present data from a family of poly(l-lysine) dendrimers and explore their suitability for this purpose. In order to test these compounds, we employed three different IM-MS platforms (Agilent 6560 IM-QToF, Waters Synapt G2, and a home-built variable temperature drift tube IM-MS) and used them to investigate six different generations of dendrimers in two buffer gases (helium and nitrogen). Each molecule gives a highly discrete CCS distribution suggestive of single conformers for each m/z value. The DTCCSN2 values of this series of molecules (molecular weight: 330-16,214 Da) range from 182 to 2941 Å2, which spans the CCS range that would be found by many synthetic molecules including supramolecular compounds and many biopolymers. The CCS values for each charge state were highly reproducible in day-to-day analysis on each instrument, although we found small variations in the absolute CCS values between instruments. The rigidity of each dendrimer was probed using collisionally activated and high-temperature IM-MS experiments, where no evidence for a significant CCS change ensued. Taken together, this data indicates that these polymers are candidates for CCS calibration and could also help to reconcile differences found in CCS measurements on different instrument geometries.


Assuntos
Dendrímeros , Espectrometria de Mobilidade Iônica , Polilisina , Dendrímeros/química , Polilisina/química , Espectrometria de Mobilidade Iônica/métodos , Espectrometria de Massas/métodos , Conformação Molecular
13.
Phytochemistry ; 224: 114140, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38750709

RESUMO

Eight previously undescribed cevanine-type steroidal alkaloids, cirrhosinones I-N and cirrhosinols A-B, along with five known analogs, were isolated from the bulbs of Fritillaria cirrhosa D. Don. Their structures were elucidated on the basis of comprehensive analysis of HRESIMS, 1D and 2D NMR spectroscopic data, and single-crystal X-ray diffraction analyses. All compounds revealed weak NO inhibitory activities in the LPS-stimulated NR8383 cells at the concentration of 20 µM, with inhibition ratios ranging from 5.1% to 14.3%.


Assuntos
Alcaloides , Fritillaria , Raízes de Plantas , Fritillaria/química , Raízes de Plantas/química , Estrutura Molecular , Alcaloides/química , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Cevanas/química , Cevanas/farmacologia , Cevanas/isolamento & purificação , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Animais , Conformação Molecular , Cristalografia por Raios X , Linhagem Celular , Ratos , Esteroides/química , Esteroides/isolamento & purificação , Esteroides/farmacologia , Relação Dose-Resposta a Droga , Relação Estrutura-Atividade , Modelos Moleculares
14.
Yakugaku Zasshi ; 144(5): 545-551, 2024.
Artigo em Japonês | MEDLINE | ID: mdl-38692931

RESUMO

The membrane permeability, and its evaluation, is crucial factor in the process of uptake of compounds from outside to inside the cell and in the inhibition of the activity of disease-causing target proteins. Although molecular dynamics (MD) simulations have been shown to be able to reproduce the conformational changes of compounds occurring during membrane permeation, it is still challenging to extract the membrane permeability at an affordable computational workload solely by conventional MD. Indeed, the time scale accessible by MD is far below the one characterizing the actual permeation process. Phenomena occurring in living organisms escaping the reach of standard MD are generally referred to as biological rare events, and the membrane permeation process is one of them. To overcome this time-scale problem, several enhanced sampling methods have been proposed over the years to improve conformational sampling. In this review, a hybrid sampling method that combines the parallel cascade selection MD (PaCS-MD) and the outlier flooding method (OFLOOD), introduced and developed by our group, is proposed as a tool to study the membrane permeation from structural sampling (rare-event sampling). The obtained trajectories are used to estimate the free energy profiles for the membrane permeation and to compute the membrane permeation coefficients. Moreover, we present an example of application of the free energy reaction network method as a versatile way for incorporating explicitly into reaction coordinates the degrees of freedom related to internal motion.


Assuntos
Permeabilidade da Membrana Celular , Simulação de Dinâmica Molecular , Conformação Molecular , Termodinâmica
15.
Int J Biol Macromol ; 271(Pt 1): 132570, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38782316

RESUMO

Resistant starch (RS) is important in controlling diabetes. The primary objective of this study is to examine the impact of molecular conformation on the enzymatic hydrolysis efficiency of starch by α-amylase. And the interactions between starch molecules with different conformations and α-amylase were analysed by using molecule dynamics simulation and molecular docking. It was found, the natural conformational starch molecule was hydrolysed from the middle of the starch chain by α-amylase, producing polysaccharides. The bent PS-conformational starch molecules with multiple O2-O3 intramolecular hydrogen bonds produced by high-pressure was hydrolysed from the head of the starch chain to produce glucose, which is not conducive to RS formation. The stretched H-conformation without intramolecular hydrogen bonds produced by heat treatment was not hydrolysed by α-amylase. However, it occupied the active groove and formed strong interactions with α-amylase, which prevented other starch molecules from binding to α-amylase, thus reducing hydrolysis efficiency. Moreover, the total interaction energies between the three starch molecules and α-amylase were approximately 78 kJ/mol. And several hydrogen bonds were formed between the starch molecules and α-amylase, which provides evidence for the continuous sliding hydrolysis hypothesis of α-amylase. Moreover, these results provide an important reference for elucidating the mechanism of RS formation.


Assuntos
Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Amido , alfa-Amilases , Amido/química , Amido/metabolismo , Hidrólise , alfa-Amilases/química , alfa-Amilases/metabolismo , Simulação de Dinâmica Molecular , Conformação Molecular
16.
J Chem Inf Model ; 64(9): 3779-3789, 2024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38624083

RESUMO

Ligand-based virtual screening (LBVS) can be pivotal for identifying potential drug leads, especially when the target protein's structure is unknown. However, current LBVS methods are limited in their ability to consider the ligand conformational flexibility. This study presents AutoDock-SS (Similarity Searching), which adapts protein-ligand docking for use in LBVS. AutoDock-SS integrates novel ligand-based grid maps and AutoDock-GPU into a novel three-dimensional LBVS workflow. Unlike other approaches based on pregenerated conformer libraries, AutoDock-SS's built-in conformational search optimizes conformations dynamically based on the reference ligand, thus providing a more accurate representation of relevant ligand conformations. AutoDock-SS supports two modes: single and multiple ligand queries, allowing for the seamless consideration of multiple reference ligands. When tested on the Directory of Useful Decoys─Enhanced (DUD-E) data set, AutoDock-SS surpassed alternative 3D LBVS methods, achieving a mean AUROC of 0.775 and an EF1% of 25.72 in single-reference mode. The multireference mode, evaluated on the augmented DUD-E+ data set, demonstrated superior accuracy with a mean AUROC of 0.843 and an EF1% of 34.59. This enhanced performance underscores AutoDock-SS's ability to treat compounds as conformationally flexible while considering the ligand's shape, pharmacophore, and electrostatic potential, expanding the potential of LBVS methods.


Assuntos
Simulação de Acoplamento Molecular , Ligantes , Avaliação Pré-Clínica de Medicamentos/métodos , Proteínas/química , Proteínas/metabolismo , Interface Usuário-Computador , Conformação Proteica , Conformação Molecular
17.
J Chem Inf Model ; 64(9): 3610-3620, 2024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38668753

RESUMO

The fast and accurate conformation space modeling is an essential part of computational approaches for solving ligand and structure-based drug discovery problems. Recent state-of-the-art diffusion models for molecular conformation generation show promising distribution coverage and physical plausibility metrics but suffer from a slow sampling procedure. We propose a novel adversarial generative framework, COSMIC, that shows comparable generative performance but provides a time-efficient sampling and training procedure. Given a molecular graph and random noise, the generator produces a conformation in two stages. First, it constructs a conformation in a rotation and translation invariant representation─internal coordinates. In the second step, the model predicts the distances between neighboring atoms and performs a few fast optimization steps to refine the initial conformation. The proposed model considers conformation energy, achieving comparable space coverage, and diversity metrics results.


Assuntos
Modelos Moleculares , Conformação Molecular , Ligantes , Descoberta de Drogas , Algoritmos
18.
Phytochemistry ; 223: 114106, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38657885

RESUMO

Daphmacrimines A-K (1-11) were isolated from the leaves and stems of Daphniphyllum macropodum Miq. Their structures and stereochemistries were determined by extensive techniques, including HRESIMS, NMR, ECD, IR, and single-crystal X-ray crystallography. Daphmacrimines A-D (1-4) are unprecedented Daphniphyllum alkaloids with a 2-oxazolidinone ring. Daphmacrimine I (9) contains a nitrile group, which is relatively rare in naturally occurring alkaloids. The abilities of daphmacrimines A-D and daphmacrimines G-K to enhance lysosomal biogenesis were evaluated through LysoTracker Red staining. Daphmacrimine K (11) can induce lysosomal biogenesis and promote autophagic flux.


Assuntos
Alcaloides , Daphniphyllum , Alcaloides/química , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Estrutura Molecular , Daphniphyllum/química , Folhas de Planta/química , Humanos , Cristalografia por Raios X , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Caules de Planta/química , Conformação Molecular
19.
Bioorg Chem ; 147: 107388, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38678775

RESUMO

In this study, we investigated the potential of long-range fluorine-carbon J-coupling for determining the structures of deoxyfluorinated disaccharides. Three disaccharides, previously synthesized as potential galectin inhibitors, exhibited through-space fluorine-carbon J-couplings. In our independent conformational analysis of these disaccharide derivatives, we employed a combination of density functional theory (DFT) calculations and nuclear magnetic resonance (NMR) experiments. By comparing the calculated nuclear shieldings with the experimental carbon chemical shifts, we were able to identify the most probable conformers for each compound. A model comprising fluoromethane and methane molecules was used to study the relationship between molecular arrangements and intermolecular through-space J-coupling. Our study demonstrates the important effect of internuclear distance and molecular orientation on the magnitude of fluorine-carbon coupling. The experimental values for the fluorine-carbon through-space couplings (TSCs) of the disaccharides corresponded with values calculated for the most probable conformers identified by the conformational analysis. These results unlock the broader application of fluorine-carbon TSCs as powerful tools for conformational analysis of flexible molecules, offering valuable insights for future structural investigations.


Assuntos
Teoria da Densidade Funcional , Dissacarídeos , Flúor , Espectroscopia de Ressonância Magnética , Flúor/química , Dissacarídeos/química , Carbono/química , Configuração de Carboidratos , Conformação Molecular
20.
Acta Crystallogr C Struct Chem ; 80(Pt 4): 129-142, 2024 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-38577890

RESUMO

This report presents a comprehensive investigation into the synthesis and characterization of Schiff base compounds derived from benzenesulfonamide. The synthesis process, involved the reaction between N-cycloamino-2-sulfanilamide and various substituted o-salicylaldehydes, resulted in a set of compounds that were subjected to rigorous characterization using advanced spectral techniques, including 1H NMR, 13C NMR and FT-IR spectroscopy, and single-crystal X-ray diffraction. Furthermore, an in-depth assessment of the synthesized compounds was conducted through Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) analysis, in conjunction with docking studies, to elucidate their pharmacokinetic profiles and potential. Impressively, the ADMET analysis showcased encouraging drug-likeness properties of the newly synthesized Schiff bases. These computational findings were substantiated by molecular properties derived from density functional theory (DFT) calculations using the B3LYP/6-31G* method within the Jaguar Module of Schrödinger 2023-2 from Maestro (Schrodinger LLC, New York, USA). The exploration of frontier molecular orbitals (HOMO and LUMO) enabled the computation of global reactivity descriptors (GRDs), encompassing charge separation (Egap) and global softness (S). Notably, within this analysis, one Schiff base, namely, 4-bromo-2-{N-[2-(pyrrolidine-1-sulfonyl)phenyl]carboximidoyl}phenol, 20, emerged with the smallest charge separation (ΔEgap = 3.5780 eV), signifying heightened potential for biological properties. Conversely, 4-bromo-2-{N-[2-(piperidine-1-sulfonyl)phenyl]carboximidoyl}phenol, 17, exhibited the largest charge separation (ΔEgap = 4.9242 eV), implying a relatively lower propensity for biological activity. Moreover, the synthesized Schiff bases displayed remarkeable inhibition of tankyrase poly(ADP-ribose) polymerase enzymes, integral in colon cancer, surpassing the efficacy of a standard drug used for the same purpose. Additionally, their bioavailability scores aligned closely with established medications such as trifluridine and 5-fluorouracil. The exploration of molecular electrostatic potential through colour mapping delved into the electronic behaviour and reactivity tendencies intrinsic to this diverse range of molecules.


Assuntos
Neoplasias do Colo , Bases de Schiff , Humanos , Bases de Schiff/química , Modelos Moleculares , Conformação Molecular , Cristalografia por Raios X , Espectroscopia de Infravermelho com Transformada de Fourier , Ligação de Hidrogênio , Fenóis
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