Showing papers by "Kaixian Chen published in 2019"

D3Pockets: A Method and Web Server for Systematic Analysis of Protein Pocket Dynamics

Abstract: The intrinsic dynamic properties of the ligand-binding pockets of proteins are important for the protein function mechanism and thus are useful to drug discovery and development. Few methods are available to study the dynamic properties, such as pocket stability, continuity, and correlation. In this work, we develop a method and web server, namely, D3Pockets, for exploring the dynamic properties of the protein pocket based on either molecular dynamics (MD) simulation trajectories or conformational ensembles. Application of D3Pockets on five target proteins as examples, namely, HIV-1 protease, BACE1, L-ABP, GPX4, and GR, uncovers more information on the dynamic properties of the ligand-binding pockets, which should be helpful to understanding protein function mechanism and drug design. The D3Pockets web server is available at http://www.d3pharma.com/D3Pocket/index.php .

The dynamic conformational landscape of the protein methyltransferase SETD8.

Abstract: Elucidating the conformational heterogeneity of proteins is essential for understanding protein function and developing exogenous ligands. With the rapid development of experimental and computational methods, it is of great interest to integrate these approaches to illuminate the conformational landscapes of target proteins. SETD8 is a protein lysine methyltransferase (PKMT), which functions in vivo via the methylation of histone and nonhistone targets. Utilizing covalent inhibitors and depleting native ligands to trap hidden conformational states, we obtained diverse X-ray structures of SETD8. These structures were used to seed distributed atomistic molecular dynamics simulations that generated a total of six milliseconds of trajectory data. Markov state models, built via an automated machine learning approach and corroborated experimentally, reveal how slow conformational motions and conformational states are relevant to catalysis. These findings provide molecular insight on enzymatic catalysis and allosteric mechanisms of a PKMT via its detailed conformational landscape.

Advance in biological activities of natural guaiane-type sesquiterpenes

Abstract: Belonging to the terpenes family, sesquiterpenes represent a group of natural compounds with diverse skeletal types. Given their unique structural features and various functional groups, these compounds possess numerous biological activities and have received increasing interest in recent years. Guaiane-type sesquiterpenes are a special category of sesquiterpenes with various biological activities, such as antitumor, anti-inflammatory, and antibacterial. Mipsagargin, a prodrug of thapsigargin, could be used in the treatment of glioblastoma multiforme and hepatocellular carcinoma, and has completed the phase II clinical trials. Guaiane-type sesquiterpenes are not only abundant but also diverse, widely distributed, and complex, and have variable structures. To our knowledge, there is no review of guaiane-type sesquiterpenes in extant literature. This review summarizes the distribution of guaiane-type sesquiterpenes in plants, the possible biogenic pathways and chemical structures as well as the research progress on their biological activities from 1990 to 2018. Guaiane-type sesquiterpenes are present in approximately 70 genera of 30 plant families (e.g., Asteraceae, Lamiaceae, Thymelaeaceae, and Zingiberaceae); they can be classified into 12,6-guaianolides, 12,8-guaianolides, pseudoguaianolides, tricycle guaiane-type sesquiterpenes, dimers or trimers containing guaiane-type sesquiterpenes mother nuclei, variant guaiane-type sesquiterpenes, and other guaiane-type sesquiterpenes. Among them, 12,8-guaianolides exerted the broadest biological activity.

Improving the Virtual Screening Ability of Target-Specific Scoring Functions Using Deep Learning Methods.

Abstract: Scoring functions play an important role in structure-based virtual screening. It has been widely accepted that target-specific scoring functions (TSSFs) may achieve better performance compared with universal scoring functions in actual drug research and development processes. A method that can effectively construct TSSFs will be of great value to drug design and discovery. In this work, we proposed a deep learning-based model named DeepScore to achieve this goal. DeepScore adopted the form of PMF scoring function to calculate protein-ligand binding affinity. However, different from PMF scoring function, in DeepScore, the score for each protein-ligand atom pair was calculated using a feedforward neural network. Our model significantly outperformed Glide Gscore on validation data set DUD-E. The average ROC-AUC on 102 targets was 0.98. We also combined Gscore and DeepScore together using a consensus method and put forward a consensus model named DeepScoreCS. The comparison results showed that DeepScore outperformed other machine learning-based TSSFs building methods. Furthermore, we presented a strategy to visualize the prediction of DeepScore. All of these results clearly demonstrated that DeepScore would be a useful model in constructing TSSFs and represented a novel way incorporating deep learning and drug design.

KinomeX: a web application for predicting kinome-wide polypharmacology effect of small molecules.

Abstract: Motivation The large-scale kinome-wide virtual profiling for small molecules is a daunting task by experimental and traditional in silico drug design approaches. Recent advances in deep learning algorithms have brought about new opportunities in promoting this process. Results KinomeX is an online platform to predict kinome-wide polypharmacology effect of small molecules based solely on their chemical structures. The prediction is made by a multi-task deep neural network model trained with over 140 000 bioactivity data points for 391 kinases. Extensive computational and experimental validations have been performed. Overall, KinomeX enables users to create a comprehensive kinome interaction network for designing novel chemical modulators, and is of practical value on exploring the previously less studied or untargeted kinases. Availability and implementation KinomeX is available at: https://kinome.dddc.ac.cn. Supplementary information Supplementary data are available at Bioinformatics online.

Procyanidin C1, a Component of Cinnamon Extracts, Is a Potential Insulin Sensitizer That Targets Adipocytes.

Abstract: Natural products are one of the main sources for discovering new lead compounds. We previously reported that cinnamon extract has a promising effect in regulating lipid tissue volume and insulin sensitivity in vivo. However, its effective component and the underlying mechanism are not known. In the present study, we analyzed the effect of different components of cinnamon on regulating insulin sensitivity in 3T3-L1 adipocytes. Functional assay revealed that, of the six major components of cinnamon extracts, the B-type procyanidin, procyanidin C1, improves the differentiation of 3T3-L1 cells (TG content: 1.10 ± 0.09 mM at a dosage of 25 μM vs 0.67 ± 0.02 mM in vehicle group, p < 0.001) and promotes insulin-induced glucose uptake (8.58 ± 1.43 at a dosage of 25 μM vs 3.05 ± 1.24 in vehicle group, p < 0.001). Mechanism studies further suggested that procyanidin C1 activates the AKT-eNOS pathway, thus up-regulating glucose uptake and enhancing insulin sensitivity in mature adipocytes. Taken together, our study identified B-type procyanidin C1, a component of cinnamon extract, that stimulates preadipocyte differentiation and acts as a potential insulin action enhancer through the AKT-eNOS pathway in mature adipocytes.

Review of the Ethnopharmacology, Phytochemistry, and Pharmacology of the Genus Veronica.

Abstract: Veronica is the largest genus in the flowering plant family Plantaginaceae and comprises approximately 500 species. The genus was formerly placed in the Scrophulariaceae family, some species of whi...

Alkaloid Enantiomers from the Roots of Isatis indigotica.

Abstract: Five pairs of alkaloid enantiomers (1a/1b–5a/5b) were obtained from Isatis indigotica (I. indigotica) roots. Among them, 1a/1b, 2a/2b and 3a/3b were determined as three pairs of new alkaloid enantiomers. Their structures were elucidated by physicochemical properties and spectroscopic methods. The absolute configurations were deduced by comparison of their experimental circular dichroism (CD) and calculated electronic circular dichroism (ECD) spectra, as well as by single-crystal X-ray crystallography using anomalous scattering of Cu Kα radiation. Alkaloids 1a and 1b possess an unpresented carbon skeleton and their putative biosynthetic pathways are discussed. Moreover, all of the alkaloids were tested for their nitric oxide (NO) inhibitory effects in RAW 264.7 cells, and 4a and 4b showed inhibitory effects with IC50 values of 76.97 μM and 65.88 μM, respectively.

Discovery of trisubstituted nicotinonitrile derivatives as novel human GCN5 inhibitors through AlphaScreen-based high throughput screening

Abstract: The general control nonrepressed protein 5 (GCN5) is an important target for drug design and drug discovery largely owing to its pathogenic role in malignancies. Chemical probes that target GCN5 have been developed in recent decades, but their potencies are still unsatisfactory. In this study, through an in-house developed AlphaScreen-based high throughput screening platform, radioactive acetylation assays and 2D-similarity based analogue searching, we discovered DC_HG24-01 as the novel hGCN5 inhibitor with the IC50 value of 3.1 ± 0.2 μM. Further docking studies suggested that DC_HG24-01 could occupy the binding pocket of acetyl-CoA cofactor, which laid the foundation for the development of more potent hGCN5 inhibitors in the future. At the cellular level, DC_HG24-01 could retard cell proliferation and block the acetylation of H3K14 leading to cell apoptosis and cell cycle arrest at the G1 phase in MV4-11 cell lines. Taken together, the discovery of DC_HG24-01 may serve as a good starting point to accelerate the development of more potent hGCN5 inhibitors through further structural decoration and provide new insight into the pharmacological treatment of leukemia.

The inhibitory mechanism of aurintricarboxylic acid targeting serine/threonine phosphatase Stp1 in Staphylococcus aureus: insights from molecular dynamics simulations

Abstract: Serine/threonine phosphatase (Stp1) is a member of the bacterial Mg2+- or Mn2+- dependent protein phosphatase/protein phosphatase 2C family, which is involved in the regulation of Staphylococcus aureus virulence. Aurintricarboxylic acid (ATA) is a known Stp1 inhibitor with an IC50 of 1.03 μM, but its inhibitory mechanism has not been elucidated in detail because the Stp1–ATA cocrystal structure has not been determined thus far. In this study, we performed 400 ns molecular dynamics (MD) simulations of the apo–Stp1 and Stp1–ATA complex models. During MD simulations, the flap subdomain of the Stp1–ATA complex experienced a clear conformational transition from an open state to a closed state, whereas the flap domain of apo–Stp1 changed from an open state to a semi-open state. In the Stp1–ATA complex model, the hydrogen bond (H-bond) between D137 and N142 disappeared, whereas critical H-bond interactions were formed between Q160 and H13, Q160/R161 and ATA, as well as N162 and D198. Finally, four residues (D137, N142, Q160, and R161) in Stp1 were mutated to alanine and the mutant enzymes were assessed using phosphate enzyme activity assays, which confirmed their important roles in maintaining Stp1 activity. This study indicated the inhibitory mechanism of ATA targeting Stp1 using MD simulations and sheds light on the future design of allosteric Stp1 inhibitors.

Trans-indoline cyclopropylamine chemical compound, and method for preparation, pharmaceutical composition, and use thereof

Abstract: The present invention relates to the fields of medicinal chemistry and pharmacotherapy, and specifically relates to the chemical compound of formula (I), and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt, and mixtures thereof, as well as its method for preparation, a pharmaceutical composition containing said chemical compound, and use as a lysine-specific demethylase 1 (LSD1) inhibitor. The cyclopropylamine chemical compound to which the present invention relates may be used in the treatment of cancer.

Structural Insight into the Mechanism of Staphylococcus aureus Stp1 Phosphatase.

Abstract: Staphylococcus aureus Stp1, which belongs to the bacterial metal-dependent protein phosphatase (PPM) family, is a promising candidate for antivirulence targeting. How Stp1 recognizes the phosphoryl...

5-membered heterocycle fused with [3,4-d] pyridazinone, and manufacturing method, pharmaceutical composition, and application thereof

Abstract: The present invention provides a compound comprising a 5-membered heterocycle fused with a pyridazinone, wherein the compound is used as an FGFR kinase inhibitor, and a manufacturing method and application thereof. The invention specifically provides a compound as represented by formula (I). Various radicals are as defined in the specification. The compound provided by the invention effectively inhibits an activity of an FGFR kinase, and can be used to manufacture a pharmaceutical product for treating a disease related to the activity of the FGFR kinase.

불소로 치환된 시클로프로필아민계 화합물 및 이의 제조 방법, 약물 조성물 및 용도

Abstract: 본 발명은 약물 화학 및 약물 치료 분야에 관한 것으로, 구체적으로 일반식I의 화합물, 이의 라세미체, R-이성질체, S-이성질체, 약용 가능한 염 및 이들의 혼합물, 이의 제조 방법, 이러한 화합물을 함유한 약물 조성물 및 라이신 특이적 디메틸라아제-1(LSD1) 억제제로서의 용도에 관한 것이다. 암증 치료에서의 본 발명에 관한 불소로 치환된 시클로프로필아민계의 용도에 관한 것이다.일반식I

Polymorph of DPPIV inhibitor maleate and preparation method therefor

Abstract: The invention describes a polymorph of (R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl)-4-carbonyl-3,4-dihydrothiophene[3,2-d]pyrimidine-6-carboxylic acid maleate and a preparation method therefor. The polymorph is a crystal having high stability and low hygroscopicity, and the crystal form is selected from crystal form A, crystal form B and crystal form C. Furthermore, the crystal form has a strong in-vivo hypoglycemic activity and can be used for the preparation of a novel drug for the treatment or prevention of diabetes mellitus type H and/or complications of diabetes mellitus type H.

Catalpol derivative and application thereof

Abstract: The invention belongs to the technical field of the medicine and chemical industry, discloses a natural catalpol derivative and a novel modified catalpol derivative derived from catalposide and picroside II, and provides a preparation method of the derivative and application of the derivative in the preparation of anti-inflammatory drugs. The structure of the natural catalpol derivative is shown in a formula (I) or a formula (II), and the structure of the novel modified catalpol derivative derived from the catalposide and the picroside II is shown in a formula (III) or a formula (IV). Experimental results show that compounds of which the structures are shown in formula (I), formula (II), formula (III) and formula (IV) or hydrates of the compounds, pharmaceutically acceptable salt, tautomers, stereisomers and precursor compounds have a significant inhibiting effect on 8-hydroxytridine DNA glycosylase 1 (8-hydroxytridine DNA glycosylase 1, OGG1), and has wide application space in the preparation of the anti-inflammatory drugs and antitumor drugs.