Recent trends suggest that Chinese herbal medicine formulas(CHM formulas)are promising treatments for complex diseases.To characterize the precise syndromes,precise diseases and precise targets of the precise targets ...Recent trends suggest that Chinese herbal medicine formulas(CHM formulas)are promising treatments for complex diseases.To characterize the precise syndromes,precise diseases and precise targets of the precise targets between complex diseases and CHM formulas,we developed an artificial intelligence-based quantitative predictive algorithm(DeepTCM).DeepTCM has gone through multilevel model calibration and validation against a comprehensive set of herb and disease data so that it accurately captures the complex cellular signaling,molecular and theoretical levels of traditional Chinese medicine(TCM).As an example,our model simulated the optimal CHM formulas for the treatment of coronary heart disease(CHD)with depression,and through model sensitivity analysis,we calculated the balanced scoring of the formulas.Furthermore,we constructed a biological knowledge graph representing interactions by associating herb-target and gene-disease interactions.Finally,we experimentally confirmed the therapeutic effect and pharmacological mechanism of a novel model-predicted intervention in humans and mice.This novel multiscale model opened up a new avenue to combine“disease syndrome”and“macro micro”system modeling to facilitate translational research in CHM formulas.展开更多
Theβ-lactam antibiotic resistance caused by NDM-1 has become a major crisis of global public health.We have previously screened out(-)-epicatechin gallate(ECG)as a potent NDM-1 inhibitor.We further discussed its inhi...Theβ-lactam antibiotic resistance caused by NDM-1 has become a major crisis of global public health.We have previously screened out(-)-epicatechin gallate(ECG)as a potent NDM-1 inhibitor.We further discussed its inhibitory effect and action mode in the present study.According to our results,ECG reversibly inactivated NDM-1 in a non-competitive mode,with an IC50 value of 4.48μM.ECG effectively recovered the activity of severalβ-lactam antibiotics against resistant strain harboring blaNDM-1.Especially,the effects on carbapenems were worth mentioning.The zinc supplement assay indicated a zinc-related mechanism of ECG.Different from traditional chelating agents,it showed low toxicity both in vivo and in vitro.In a word,our findings provided a promising NDM-1 inhibitor,ECG,which was able to assist carbapenems against NDM-1-producing strain.展开更多
As a zinc-dependent enzyme, metal-β-lactamase L1 contributes to the development of β-lactam antibiotic resistance. The metal-β-lactamase inhibitor can restore the efficacy of β-lactam antibiotics, and its developm...As a zinc-dependent enzyme, metal-β-lactamase L1 contributes to the development of β-lactam antibiotic resistance. The metal-β-lactamase inhibitor can restore the efficacy of β-lactam antibiotics, and its development has attracted much attention. In the present study, we used four widely-used virtual screening programs to screen 7035 small molecules to identify potential L1 inhibitors, and a high-throughput experimental model of L1 inhibitors was established. In this high-throughput testing model, the inhibition rate of 163 compounds on L1 exceeded 40%. The results of virtual screening of 7035 small molecules using the following four programs showed that among the top 1.35% of the compounds, their hit rates were ranked as Schr?dinger’s(5.26%), DS(1.05%), and Sybyl-x 2.0(1.05%), and Smina(2.11%).展开更多
基金supported by the National Natural Science Foundation of China(Grant No.:82174246)the National Key R&D Program of China(Grant No.:2019YFC1708701)the Postdoctoral Innovation Talent Support Program(Grant No.:BX20220329).
文摘Recent trends suggest that Chinese herbal medicine formulas(CHM formulas)are promising treatments for complex diseases.To characterize the precise syndromes,precise diseases and precise targets of the precise targets between complex diseases and CHM formulas,we developed an artificial intelligence-based quantitative predictive algorithm(DeepTCM).DeepTCM has gone through multilevel model calibration and validation against a comprehensive set of herb and disease data so that it accurately captures the complex cellular signaling,molecular and theoretical levels of traditional Chinese medicine(TCM).As an example,our model simulated the optimal CHM formulas for the treatment of coronary heart disease(CHD)with depression,and through model sensitivity analysis,we calculated the balanced scoring of the formulas.Furthermore,we constructed a biological knowledge graph representing interactions by associating herb-target and gene-disease interactions.Finally,we experimentally confirmed the therapeutic effect and pharmacological mechanism of a novel model-predicted intervention in humans and mice.This novel multiscale model opened up a new avenue to combine“disease syndrome”and“macro micro”system modeling to facilitate translational research in CHM formulas.
基金CAMS Innovation Fund for Medical Sciences (Grant No. 2021-I2M-1-028)the National Natural Science Foundation of China (Grant No. 32141003, 81872913 and 81903678)。
基金Natural Sciences Foundation of China(NSFC,Grant No.81872913)National High-tech R&D Program(863 Program,Grant No.2015AA020911)。
文摘Theβ-lactam antibiotic resistance caused by NDM-1 has become a major crisis of global public health.We have previously screened out(-)-epicatechin gallate(ECG)as a potent NDM-1 inhibitor.We further discussed its inhibitory effect and action mode in the present study.According to our results,ECG reversibly inactivated NDM-1 in a non-competitive mode,with an IC50 value of 4.48μM.ECG effectively recovered the activity of severalβ-lactam antibiotics against resistant strain harboring blaNDM-1.Especially,the effects on carbapenems were worth mentioning.The zinc supplement assay indicated a zinc-related mechanism of ECG.Different from traditional chelating agents,it showed low toxicity both in vivo and in vitro.In a word,our findings provided a promising NDM-1 inhibitor,ECG,which was able to assist carbapenems against NDM-1-producing strain.
基金Natural Sciences Foundation of China (Grant No. 81872913)National High-tech R&D Program (863 Program, Grant No. 2015AA020911)。
文摘As a zinc-dependent enzyme, metal-β-lactamase L1 contributes to the development of β-lactam antibiotic resistance. The metal-β-lactamase inhibitor can restore the efficacy of β-lactam antibiotics, and its development has attracted much attention. In the present study, we used four widely-used virtual screening programs to screen 7035 small molecules to identify potential L1 inhibitors, and a high-throughput experimental model of L1 inhibitors was established. In this high-throughput testing model, the inhibition rate of 163 compounds on L1 exceeded 40%. The results of virtual screening of 7035 small molecules using the following four programs showed that among the top 1.35% of the compounds, their hit rates were ranked as Schr?dinger’s(5.26%), DS(1.05%), and Sybyl-x 2.0(1.05%), and Smina(2.11%).
