Kaixian Chen

Bio: Kaixian Chen is an academic researcher from Chinese Academy of Sciences. The author has contributed to research in topics: Virtual screening & Docking (molecular). The author has an hindex of 47, co-authored 380 publications receiving 9209 citations. Previous affiliations of Kaixian Chen include Shanghai University & East China University of Science and Technology.

One-Pot Approach for C-CBond Formation through Ruthenium-Amido Complex Catalyzed TandemAldol Reaction/Hydrogenation

Abstract: A one-pot novel and efficient approach was developed for the α-alkylation of various nitriles with carbonyl compounds using ruthenium-amido complex catalyst 1. The C―C bond was formed through aldol reaction followed by hydrogenation with triethylamine―formic acid (TEAF) and 1. Moderate to high yields were obtained, and a variety of functional groups were tolerated, including nitro and chloro groups, and a furan ring.

The essential role for aromatic cluster in the β3 adrenergic receptor

Abstract: To explore the function of the conserved aromatic cluster F2135.47, F3086.51, and F3096.52 in human β3 adrenergic receptor (hβ3AR). Point mutation technology was used to produce plasmid mutations of hβ3AR. HEK-293 cells were transiently co-transfected with the hβ3AR (wild-type or mutant) plasmids and luciferase reporter vector pCRE-luc. The expression levels of hβ3AR in the cells were determined by Western blot analysis. The constitutive signalling and the signalling induced by the β3AR selective agonist, BRL (BRL37344), were then evaluated. To further explore the interaction mechanism between BRL and β3AR, a three-dimensional complex model of β3AR and BRL was constructed by homology modelling and molecular docking. For F3086.51, Ala and Leu substitution significantly decreased the constitutive activities of β3AR to approximately 10% of that for the wild-type receptor. However, both the potency and maximal efficacy were unchanged by Ala substitution. In the F3086.51L construct, the EC50 value manifested as a “right shift” of approximately two orders of magnitude with an increased Emax. Impressively, the molecular pharmacological phenotype was similar to the wild-type receptor for the introduction of Tyr at position 3086.51, though the EC50 value increased by approximately five-fold for the mutant. For F3096.52, the constitutive signalling for both F3096.52A and F3096.52L constructs were strongly impaired. In the F3096.52A construct, BRL-stimulated signalling showed a normal Emax but reduced potency. Leu substitution of F3096.52 reduced both the Emax and potency. When F3096.52 was mutated to Tyr, the constitutive activity was decreased approximately three-fold, and BRL-stimulated signalling was significantly impaired. Furthermore, the double mutant (F3086.51A_F3096.52A) caused the total loss of β3AR function. The predicted binding mode between β3AR and BRL revealed that both F3086.51 and F3096.52 were in the BRL binding pocket of β3AR, while F2135.47 and W3056.48 were distant from the binding site. These results revealed that aromatic residues, especially F3086.51 and F3096.52, play essential roles in the function of β3AR. Aromatic residues maintained the receptor in a partially activated state and significantly contributed to ligand binding. The results supported the common hypothesis that the aromatic cluster F[Y]5.47/F[Y]6.52/F[Y]6.51 conserved in class A G protein-coupled receptor (GPCR) plays an important role in the structural stability and activation of GPCRs.

Synthesis and Structures of (S)- and (r)-2-[3-Cyano-4-(2-Thienyl)-5,6,7, 8-Tetrahydroquinolin-2-Ylsulfanyl]-3-Methyl-N-Phenylbutyramide:

Abstract: (S)- and (R)-2-[3-cyano-4-(2-thienyl)-5,6,7,8-tetrahydroquinolin-2-ylsulfanyl]-N-phenyl-3-methylbutyramide (1a and 1b) were prepared from 2-thiophenaldehyde and D- and L-valines, respectively, and their crystal structures were elucidated by X-ray crystallography.

Cyclin-dependent kinase inhibitor roscovitine attenuates liver inflammation and fibrosis by influencing initiating steps of liver injury.

Abstract: Liver diseases present a significant public health burden worldwide. Although the mechanisms of liver diseases are complex, it is generally accepted that inflammation is commonly involved in the pathogenesis. Ongoing inflammatory responses exacerbate liver injury, or even result in fibrosis and cirrhosis. Here we report that roscovitine, a cyclin-dependent kinase (CDK) inhibitor, exerts beneficial effects on acute and chronic liver inflammation as well as fibrosis. Animal models of lipopolysaccharide (LPS)/d-galactosamine- and acute or chronic CCl4-induced liver injury showed that roscovitine administration markedly attenuated liver injury, inflammation and histological damage in LPS/d-galactosamine- and CCl4-induced acute liver injury models, which is consistent with the results in vitro. RNA sequencing (RNA-seq) analysis showed that roscovitine treatment repressed the transcription of a broad set of pro-inflammatory genes involved in many aspects of inflammation, including cytokine production and immune cell proliferation and migration, and inhibited the TGF-β signaling pathway and the biological process of tissue remodeling. For further validation, the beneficial effect of roscovitine against inflammation was evaluated in chronic CCl4-challenged mice. The anti-inflammation effect of roscovitine was observed in this model, accompanied with reduced liver fibrosis. The anti-fibrotic mechanism involved inhibition of profibrotic genes and blocking of hepatic stellate cell (HSC) activation. Our data show that roscovitine administration protects against liver diseases through inhibition of macrophage inflammatory actions and HSC activation at the onset of liver injury.

Pattern Recognition and Machine Learning

Abstract: Probability Distributions.- Linear Models for Regression.- Linear Models for Classification.- Neural Networks.- Kernel Methods.- Sparse Kernel Machines.- Graphical Models.- Mixture Models and EM.- Approximate Inference.- Sampling Methods.- Continuous Latent Variables.- Sequential Data.- Combining Models.

“Bioinformatics” 특집을 내면서

Abstract: BIOE 402. Medical Technology Assessment. 2 or 3 hours. Bioentrepreneur course. Assessment of medical technology in the context of commercialization. Objectives, competition, market share, funding, pricing, manufacturing, growth, and intellectual property; many issues unique to biomedical products. Course Information: 2 undergraduate hours. 3 graduate hours. Prerequisite(s): Junior standing or above and consent of the instructor.

Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors

Abstract: A new coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the aetiological agent responsible for the 2019–2020 viral pneumonia outbreak of coronavirus disease 2019 (COVID-19)1–4. Currently, there are no targeted therapeutic agents for the treatment of this disease, and effective treatment options remain very limited. Here we describe the results of a programme that aimed to rapidly discover lead compounds for clinical use, by combining structure-assisted drug design, virtual drug screening and high-throughput screening. This programme focused on identifying drug leads that target main protease (Mpro) of SARS-CoV-2: Mpro is a key enzyme of coronaviruses and has a pivotal role in mediating viral replication and transcription, making it an attractive drug target for SARS-CoV-25,6. We identified a mechanism-based inhibitor (N3) by computer-aided drug design, and then determined the crystal structure of Mpro of SARS-CoV-2 in complex with this compound. Through a combination of structure-based virtual and high-throughput screening, we assayed more than 10,000 compounds—including approved drugs, drug candidates in clinical trials and other pharmacologically active compounds—as inhibitors of Mpro. Six of these compounds inhibited Mpro, showing half-maximal inhibitory concentration values that ranged from 0.67 to 21.4 μM. One of these compounds (ebselen) also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of our screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases for which no specific drugs or vaccines are available. A programme of structure-assisted drug design and high-throughput screening identifies six compounds that inhibit the main protease of SARS-CoV-2, demonstrating the ability of this strategy to isolate drug leads with clinical potential.

New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays

Abstract: This report describes a number of substructural features which can help to identify compounds that appear as frequent hitters (promiscuous compounds) in many biochemical high throughput screens. The compounds identified by such substructural features are not recognized by filters commonly used to identify reactive compounds. Even though these substructural features were identified using only one assay detection technology, such compounds have been reported to be active from many different assays. In fact, these compounds are increasingly prevalent in the literature as potential starting points for further exploration, whereas they may not be.