Identification and Preliminary SAR Analysis of Novel Type-I Inhibitors of TIE-2 via Structure-Based Virtual Screening and Biological Evaluation in in vitro Models

2015 ◽  
Vol 55 (12) ◽  
pp. 2693-2704 ◽  
Author(s):  
Peichen Pan ◽  
Sheng Tian ◽  
Huiyong Sun ◽  
Xiaotian Kong ◽  
Wenfang Zhou ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Biological Evaluation ◽  
In Vitro Models ◽  
Type I ◽  
Sar Analysis

Design, Synthesis and Biological Evaluation of Uracil Derivatives as Novel VEGFR-2 Inhibitors

2018 ◽  
Vol 24 (6) ◽  
pp. 734-740 ◽  
Author(s):  
Jingwei Liang ◽  
Xinyang Li ◽  
Su Yang ◽  
Xin He ◽  
Mingyang Wang ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Screening Method ◽  
Growth Factor Receptor ◽  
Biological Evaluation ◽  
Type I ◽  
Lead Compound ◽  
Design Synthesis ◽  
Uracil Derivatives ◽  
Inhibitory Activities

Backgound: Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in the process of cancer angiogenesis. Type I inhibitors constitute the major ATP-competitive inhibitors and recognize mainly the active conformation of VEGFR-2. Meanwhile, type II inhibitors recognize the inactive DFG (Asp- Phe-Gly)-out conformation of VEGFR-2, which was a more promising approach for drug intervention. Methods: According to the lead compound of uracil skeleton, being screened out by structure-based virtual screening, a series of uracil derivatives were designed and synthesized. Results: The inhibitory activities were investigated against VEGFR-2 kinase in vitro. The results turned out that series A performed moderate inhibitory activities, especially compound A4 exhibited the most potent inhibitory activity (IC50=0.029 µM). Conclusion: The lead compound was screened out by structure-based pharmacophore models, then two series of uracil derivatives were synthesized according to it and evaluated for their inhibitory activities against VEGFR-2. In this study, not only a potential inhibitor has been discovered, it also demonstrates the feasibility of structure-based virtual screening method for drug discovery.

scholarly journals Discovery of New Selective Butyrylcholinesterase (BChE) Inhibitors with Anti-Aβ Aggregation Activity: Structure-Based Virtual Screening, Hit Optimization and Biological Evaluation

Molecules ◽  
2019 ◽  
Vol 24 (14) ◽  
pp. 2568 ◽  
Author(s):  
Cheng-Shi Jiang ◽  
Yong-Xi Ge ◽  
Zhi-Qiang Cheng ◽  
Yin-Yin Wang ◽  
Hong-Rui Tao ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Cell Model ◽  
Neuroblastoma Cells ◽  
Biological Evaluation ◽  
Dynamics Simulation ◽  
Dependent Manner ◽  
Binding Modes ◽  
Catalytic Active Site ◽  
Aggregation Activity

In this study, a series of selective butyrylcholinesterase (BChE) inhibitors was designed and synthesized from the structural optimization of hit 1, a 4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzoic acid derivative identified by virtual screening our compound library. The in vitro enzyme assay results showed that compounds 9 ((4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)phenyl)(pyrrolidin-1-yl)methanone) and 23 (N-(2-bromophenyl)-4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzamide) displayed improved BChE inhibitory activity and good selectivity towards BChE versus AChE. Their binding modes were probed by molecular docking and further validated by molecular dynamics simulation. Kinetic analysis together with molecular modeling studies suggested that these derivatives could target both the catalytic active site (CAS) and peripheral anionic site (PAS) of BChE. In addition, the selected compounds 9 and 23 displayed anti-Aβ1–42 aggregation activity in a dose-dependent manner, and they did not show obvious cytotoxicity towards SH-SY5Y neuroblastoma cells. Also, both compounds showed significantly protective activity against Aβ1-42-induced toxicity in a SH-SY5Y cell model. The present results provided a new valuable chemical template for the development of selective BChE inhibitors.

scholarly journals Design, Synthesis and Biological Evaluation of (2′,5′ and 3′5′-Linked) cGAMP Analogs that Activate Stimulator of Interferon Genes (STING)

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5285
Author(s):  
Xin Xie ◽  
Junyi Liu ◽  
Xiaowei Wang
Keyword(s):  
Transmembrane Protein ◽  
Biological Evaluation ◽  
Type I ◽  
Vaccine Adjuvants ◽  
One Pot ◽  
Design Synthesis ◽  
Cellular Assays ◽  
Type I Ifns ◽  
Sting Pathway

Stimulator of interferon genes (STING) is an endoplasmic reticulum adaptor transmembrane protein that plays a pivotal role in innate immune system. STING agonists, such as endogenous cyclic dinucleotide (CDN) cyclic GMP-AMP (cGAMP), have been used in diverse clinical research for immunogenic tumor clearance, antiviral treatments and vaccine adjuvants. CDNs containing noncanonical mixed 3′-5′ and 2′-5′ phosphodiester linkages show higher potency in the activation of the STING pathway. In this study, a series of 2′3′-CDNs were designed and synthesized through a modified one-pot strategy. We then established a surface plasmon resonance (SPR)-based binding assay to quantify the binding affinities of synthesized CDNs for human STING, which requested a minuscule amount of sample without any pretreatment. Using this assay, we identified compound 8d (KD = 0.038 μM), a novel CDN that showed higher binding affinity with hSTING than cGAMP (KD = 0.543 μM). Cellular assays confirmed that 8d could trigger the expression of type I IFNs and other proinflammatory cytokines more robust than cGAMP. 8d also exhibited more resistant than cGAMP to enzymatic cleavage in vitro, indicating the successful improvement in drug availability. These findings provide guidelines for the design and structural optimization of CDNs as STING agonists.

scholarly journals In Silico Identification and Biological Evaluation of Antioxidant Food Components Endowed with Human Carbonic Anhydrase IX and XII Inhibition

Antioxidants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 775 ◽  
Author(s):  
Giosuè Costa ◽  
Annalisa Maruca ◽  
Roberta Rocca ◽  
Francesca Alessandra Ambrosio ◽  
Emanuela Berrino ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Biological Evaluation ◽  
Invasion And Metastasis ◽  
Biological Assays ◽  
Food Components ◽  
Tumor Environment ◽  
Dual Inhibitors ◽  
In Silico Identification ◽  
Dehydrodiconiferyl Alcohol

The tumor-associated isoenzymes hCA IX and hCA XII catalyze the hydration of carbon dioxide to bicarbonate and protons. These isoforms are highly overexpressed in many types of cancer, where they contribute to the acidification of the tumor environment, promoting tumor cell invasion and metastasis. In this work, in order to identify novel dual hCA IX and XII inhibitors, virtual screening techniques and biological assays were combined. A structure-based virtual screening towards hCA IX and XII was performed using a database of approximately 26,000 natural compounds. The best shared hits were submitted to a thermodynamic analysis and three promising best hits were identified and evaluated in terms of their hCA IX and XII inhibitor activity. In vitro biological assays were in line with the theoretical studies and revealed that syringin, lithospermic acid, and (-)-dehydrodiconiferyl alcohol behave as good hCA IX and hCA XII dual inhibitors.

scholarly journals Discovery of novel potential selective HDAC8 inhibitors by combine ligand-based, structure-based virtual screening and in-vitro biological evaluation

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Sudhan Debnath ◽  
Tanusree Debnath ◽  
Samhita Bhaumik ◽  
Swapan Majumdar ◽  
Arunasree M. Kalle ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Predictive Ability ◽  
3D Qsar ◽  
Qsar Model ◽  
Acid Group ◽  
Biological Evaluation ◽  
In Silico Admet ◽  
Glide Docking ◽  
Hdac8 Inhibitors

AbstractNeuroblastoma is the most common extracranial solid tumor found in children and survival rate is extremely meager. HDAC8, a class I zinc-dependent enzyme, is a potential drug target for treatment of neuroblastoma and T cell lymphoma. Most of the HDAC8 inhibitors discovered till date contains a hydroxamic acid group which acts as a zinc binding group. The high binding affinity to the zinc and other ions results in adverse effects. Also, the non-selective inhibition of HDACs cause a variety of side effects. The objective of this is to identify structurally diverse, non-hydroxamate, novel, potential and selective HDAC8 inhibitors. A number of five featured pharmacophore hypotheses were generated using 32 known selective HDAC8 inhibitors. The hypotheses ADDRR.4 were selected for building 3D QSAR model. This model has an excellent correlation coefficient and good predictive ability, which was employed for virtual screening of Phase database containing 4.3 × 106 molecules. The resultant hits with fitness score >1.0 were optimized using in-silico ADMET (absorption, distribution, metabolism,  excretion, and toxicity) and XP glide docking studies. On the basis of pharmacophore matching, interacting amino acid residues, XP glide score, more affinity towards HDAC8 and less affinity towards other HDACs, and ADME results five hits- SD-01, SD-02, SD-03, SD-04 and SD-05 with new structural scaffolds,  non-hydroxamate were selected for in vitro activity study. SD-01 and SD-02 were found to be active in the nanomolar (nM) range. SD-01 had considerably good selectivity for HDAC8 over HDAC6 and SD-02 had marginal selectivity for HDAC6 over HDAC8. The compounds SD-01 and SD-02 were found to inhibit HDAC8 at concentrations (IC50) 9.0 nM and 2.7 nM, respectively.

scholarly journals SARS-CoV-2 Infection and Disease Modelling Using Stem Cell Technology and Organoids

2021 ◽  
Vol 22 (5) ◽  
pp. 2356
Author(s):  
Marta Trevisan ◽  
Silvia Riccetti ◽  
Alessandro Sinigaglia ◽  
Luisa Barzon
Keyword(s):  
Stem Cell ◽  
Cell Damage ◽  
In Vitro Models ◽  
Type I ◽  
Stem Cell Technology ◽  
Human Cardiomyocytes ◽  
Cell Technology ◽  
Alveolar Epithelial ◽  
Apoptosis And Inflammation

In this Review, we briefly describe the basic virology and pathogenesis of SARS-CoV-2, highlighting how stem cell technology and organoids can contribute to the understanding of SARS-CoV-2 cell tropisms and the mechanism of disease in the human host, supporting and clarifying findings from clinical studies in infected individuals. We summarize here the results of studies, which used these technologies to investigate SARS-CoV-2 pathogenesis in different organs. Studies with in vitro models of lung epithelia showed that alveolar epithelial type II cells, but not differentiated lung alveolar epithelial type I cells, are key targets of SARS-CoV-2, which triggers cell apoptosis and inflammation, while impairing surfactant production. Experiments with human small intestinal organoids and colonic organoids showed that the gastrointestinal tract is another relevant target for SARS-CoV-2. The virus can infect and replicate in enterocytes and cholangiocytes, inducing cell damage and inflammation. Direct viral damage was also demonstrated in in vitro models of human cardiomyocytes and choroid plexus epithelial cells. At variance, endothelial cells and neurons are poorly susceptible to viral infection, thus supporting the hypothesis that neurological symptoms and vascular damage result from the indirect effects of systemic inflammatory and immunological hyper-responses to SARS-CoV-2 infection.

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