Novel therapies are urgently needed to improve global treatment of SARS-CoV-2 infection.Herein,we briefly provide a concise report on the medicinal chemistry strategies towards the development of effective SARS-CoV-2 ...Novel therapies are urgently needed to improve global treatment of SARS-CoV-2 infection.Herein,we briefly provide a concise report on the medicinal chemistry strategies towards the development of effective SARS-CoV-2 inhibitors with representative examples in different strategies from the medicinal chemistry perspective.展开更多
The main protease(M^(pro))of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life cycle.The covalent M^(pro)inhibitor nirmatrelvir(in combination with ...The main protease(M^(pro))of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life cycle.The covalent M^(pro)inhibitor nirmatrelvir(in combination with ritonavir,a pharmacokinetic enhancer)and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic use.Effective antiviral drugs are needed to fight the pandemic,while non-covalent M^(pro)inhibitors could be promising alternatives due to their high selectivity and favorable druggability.Numerous non-covalent M^(pro)inhibitors with desirable properties have been developed based on available crystal structures of M^(pro).In this article,we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent M^(pro)inhibitors,followed by a general overview and critical analysis of the available information.Prospective viewpoints and insights into current strategies for the development of non-covalent M^(pro)inhibitors are also discussed.展开更多
Indolylarylsulfones(IASs) are classical HIV-1 non-nucleoside reverse transcriptase inhibitors(NNRTIs) with a unique scaffold and possess potent antiviral activity.To address the high cytotoxicity and improve safety pr...Indolylarylsulfones(IASs) are classical HIV-1 non-nucleoside reverse transcriptase inhibitors(NNRTIs) with a unique scaffold and possess potent antiviral activity.To address the high cytotoxicity and improve safety profiles of IASs,we introduced various sulfonamide groups linked by alkyl diamine chain to explore the entrance channel of non-nucleoside inhibitors binding pocket.48 compounds were designed and synthesized to evaluate their anti-HIV-1 activities and reverse transcriptase inhibition activities.Especially,compound R_(10)L_(4) was endowed with significant inhibitory activity towards wild-type HIV-1(EC_(50(WT))=0.007μmol/L,SI=30,930) as well as a panel of single-mutant strains exemplified by L100I(EC_(50)=0.017μmol/L,SI=13,055),E138K(EC_(50)=0.017μmol/L,SI=13,123) and Y181C(EC_(50)=0.045μmol/L,SI=4753) which were superior to Nevirapine and Etravirine.Notably,R_(10)L_(4) was characterized with significantly reduced cytotoxicity(CC_(50)=216.51μmol/L) and showed no remarkable in vivo toxic effects(acute and subacute toxicity).Moreover,the computer-based docking study was also employed to characterize the binding mode between R_(10)L_(4) and HIV-1 RT.Additionally,R_(10)L_(4) presented an acceptable pharmacokinetic profile.Collectively,these results deliver precious insights for next optimization and indicate that the sulfonamide IAS derivatives are promising NNRTIs for further development.展开更多
变电站接地网系统改造升级过程中,新建接地网对原接地网会产生一定的阻性耦合影响,导致接地系统性能下降,严重威胁电力系统的稳定运行。根据实际工程所提供的数据,基于矩量法以及CDEGS和power station 2种仿真软件对变电站新建接地网与...变电站接地网系统改造升级过程中,新建接地网对原接地网会产生一定的阻性耦合影响,导致接地系统性能下降,严重威胁电力系统的稳定运行。根据实际工程所提供的数据,基于矩量法以及CDEGS和power station 2种仿真软件对变电站新建接地网与原接地网之间的阻性耦合影响进行研究分析,并根据安全限值标准进一步讨论该变电站接地网系统的优化方案。仿真结果表明,随着新建接地网与原接地网之间水平距离的变化,其阻性耦合的影响也会发生相应的改变,并可通过增设垂直接地体以及网孔数量进一步优化变电站接地网系统,以达到电力系统的稳定运行。展开更多
Artificial intelligent aided design and manufacturing have been recognized as one kind of robust data-driven and data-intensive technologies in the integrated computational material engi-neering(ICME)era.Motivated by ...Artificial intelligent aided design and manufacturing have been recognized as one kind of robust data-driven and data-intensive technologies in the integrated computational material engi-neering(ICME)era.Motivated by the dramatical developments of the services of China Railway High-speed series for more than a decade,it is essential to reveal the foundations of lifecycle man-agement of those trains under environmental conditions.Here,the smart design and manufacturing of welded Q350 steel frames of CR200J series are introduced,presenting the capability and opportu-nity of ICME in weight reduction and lifecycle management at a cost-effective approach.In order to address the required fatigue life time enduring more than 9×10^(6)km,the response of optimized frames to the static and the dynamic loads are comprehensively investigated.It is highlighted that the maximum residual stress of the optimized welded frame is reduced to 69 MPa from 477 MPa of previous existing one.Based on the measured stress and acceleration from the railways,the fatigue life of modified frame under various loading modes could fulfil the requirements of the lifecycle man-agement.Moreover,our recent developed intelligent quality control strategy of welding process mediated by machine learning is also introduced,envisioning its application in the intelligent weld-ing.展开更多
基金financial support from the Shandong Provincial Key Research and Development Project(No.2019JZZY021011,China)Foreign Cultural and Educational Experts Project(GXL20200015001,China)+1 种基金Outstanding Youth Fund of Shandong Province(ZR2020JQ31,China)Qilu Young Scholars Program of Shandong University and the Taishan Scholar Program at Shandong Province。
文摘Novel therapies are urgently needed to improve global treatment of SARS-CoV-2 infection.Herein,we briefly provide a concise report on the medicinal chemistry strategies towards the development of effective SARS-CoV-2 inhibitors with representative examples in different strategies from the medicinal chemistry perspective.
基金We gratefully acknowledge financial support from Major Basic Research Project of Shandong Provincial Natural Science Foundation(ZR2021ZD17,China)Science Foundation for Outstanding Young Scholars of Shandong Province(ZR2020JQ31,China)+4 种基金Foreign Cultural and Educational Experts Project(GXL20200015001,China)Guangdong Basic and Applied Basic Research Foundation(2021A1515110740,China)China Postdoctoral Science Foundation(2021M702003)This work was supported in part by the Ministry of Science and Innovation of Spain through grant PID2019-104176RBI00/AEI/10.13039/501100011033 awarded to Luis Menéndez-AriasAn institutional grant of the Fundación Ramón Areces(Madrid,Spain)to the CBMSO is also acknowledged.Luis Menéndez-Arias is member of the Global Virus Network.
文摘The main protease(M^(pro))of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life cycle.The covalent M^(pro)inhibitor nirmatrelvir(in combination with ritonavir,a pharmacokinetic enhancer)and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic use.Effective antiviral drugs are needed to fight the pandemic,while non-covalent M^(pro)inhibitors could be promising alternatives due to their high selectivity and favorable druggability.Numerous non-covalent M^(pro)inhibitors with desirable properties have been developed based on available crystal structures of M^(pro).In this article,we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent M^(pro)inhibitors,followed by a general overview and critical analysis of the available information.Prospective viewpoints and insights into current strategies for the development of non-covalent M^(pro)inhibitors are also discussed.
基金financial support from Natural Science Foundation of China (81974507)Guangdong Basic and Applied Basic Research Foundation (2021A1515110740, China)+5 种基金China Postdoctoral Science Foundation (2021M702003)Shandong Province Natural Science Foundation for Youths (ZR2022QH036, China)the Foundation for Innovative Research Groups of State Key Laboratory of Microbial Technology (WZCX2021-03, China)Foreign cultural and educational experts Project (GXL20200015001, China)Science Foundation for Outstanding Young Scholars of Shandong Province (ZR2020JQ31, China)the Shandong Provincial Key research and development project (2019JZZY021011, China)。
文摘Indolylarylsulfones(IASs) are classical HIV-1 non-nucleoside reverse transcriptase inhibitors(NNRTIs) with a unique scaffold and possess potent antiviral activity.To address the high cytotoxicity and improve safety profiles of IASs,we introduced various sulfonamide groups linked by alkyl diamine chain to explore the entrance channel of non-nucleoside inhibitors binding pocket.48 compounds were designed and synthesized to evaluate their anti-HIV-1 activities and reverse transcriptase inhibition activities.Especially,compound R_(10)L_(4) was endowed with significant inhibitory activity towards wild-type HIV-1(EC_(50(WT))=0.007μmol/L,SI=30,930) as well as a panel of single-mutant strains exemplified by L100I(EC_(50)=0.017μmol/L,SI=13,055),E138K(EC_(50)=0.017μmol/L,SI=13,123) and Y181C(EC_(50)=0.045μmol/L,SI=4753) which were superior to Nevirapine and Etravirine.Notably,R_(10)L_(4) was characterized with significantly reduced cytotoxicity(CC_(50)=216.51μmol/L) and showed no remarkable in vivo toxic effects(acute and subacute toxicity).Moreover,the computer-based docking study was also employed to characterize the binding mode between R_(10)L_(4) and HIV-1 RT.Additionally,R_(10)L_(4) presented an acceptable pharmacokinetic profile.Collectively,these results deliver precious insights for next optimization and indicate that the sulfonamide IAS derivatives are promising NNRTIs for further development.
文摘变电站接地网系统改造升级过程中,新建接地网对原接地网会产生一定的阻性耦合影响,导致接地系统性能下降,严重威胁电力系统的稳定运行。根据实际工程所提供的数据,基于矩量法以及CDEGS和power station 2种仿真软件对变电站新建接地网与原接地网之间的阻性耦合影响进行研究分析,并根据安全限值标准进一步讨论该变电站接地网系统的优化方案。仿真结果表明,随着新建接地网与原接地网之间水平距离的变化,其阻性耦合的影响也会发生相应的改变,并可通过增设垂直接地体以及网孔数量进一步优化变电站接地网系统,以达到电力系统的稳定运行。
基金supported by the National Basic Scientific Research Project of China (No.JCKY2020607B003)CRRC (No.202CDA001)
文摘Artificial intelligent aided design and manufacturing have been recognized as one kind of robust data-driven and data-intensive technologies in the integrated computational material engi-neering(ICME)era.Motivated by the dramatical developments of the services of China Railway High-speed series for more than a decade,it is essential to reveal the foundations of lifecycle man-agement of those trains under environmental conditions.Here,the smart design and manufacturing of welded Q350 steel frames of CR200J series are introduced,presenting the capability and opportu-nity of ICME in weight reduction and lifecycle management at a cost-effective approach.In order to address the required fatigue life time enduring more than 9×10^(6)km,the response of optimized frames to the static and the dynamic loads are comprehensively investigated.It is highlighted that the maximum residual stress of the optimized welded frame is reduced to 69 MPa from 477 MPa of previous existing one.Based on the measured stress and acceleration from the railways,the fatigue life of modified frame under various loading modes could fulfil the requirements of the lifecycle man-agement.Moreover,our recent developed intelligent quality control strategy of welding process mediated by machine learning is also introduced,envisioning its application in the intelligent weld-ing.
