Small-molecule drugs are essential for maintaining human health. The objective of this study is to identify a molecule that can inhibit the Factor Xa protein and be easily procured. An optimization-based de novo drug ...Small-molecule drugs are essential for maintaining human health. The objective of this study is to identify a molecule that can inhibit the Factor Xa protein and be easily procured. An optimization-based de novo drug design framework, Drug CAMD, that integrates a deep learning model with a mixed-integer nonlinear programming model is used for designing drug candidates. Within this framework, a virtual chemical library is specifically tailored to inhibit Factor Xa. To further filter and narrow down the lead compounds from the designed compounds, comprehensive approaches involving molecular docking,binding pose metadynamics(BPMD), binding free energy calculations, and enzyme activity inhibition analysis are utilized. To maximize efficiency in terms of time and resources, molecules for in vitro activity testing are initially selected from commercially available portions of customized virtual chemical libraries. In vitro studies assessing inhibitor activities have confirmed that the compound EN300-331859shows potential Factor Xa inhibition, with an IC_(50)value of 34.57 μmol·L^(-1). Through in silico molecular docking and BPMD, the most plausible binding pose for the EN300-331859-Factor Xa complex are identified. The estimated binding free energy values correlate well with the results obtained from biological assays. Consequently, EN300-331859 is identified as a novel and effective sub-micromolar inhibitor of Factor Xa.展开更多
Vitamin K antagonists, such as warfarin and phen-procoumon, are the first-line oral anticoagulants for primary and secondary prevention of cerebral embo-lism in patients with atrial fibrillation. Although vitamin K an...Vitamin K antagonists, such as warfarin and phen-procoumon, are the first-line oral anticoagulants for primary and secondary prevention of cerebral embo-lism in patients with atrial fibrillation. Although vitamin K antagonists can significantly decrease the risk of stroke, their use is limited by several important drawbacks, such as a narrow therapeutic window, the risk of intracranial and gastrointestinal bleeding, interactions with a number of drugs and nutrients, and the need for regular laboratory tests for therapy adjustment. Currently, new oral anticoagulants, such as direct thrombin inhibitors (e.g., dabigatran) and direct factor Xa inhibitors (e.g., apixaban, rivaroxaban), are being developed and tested in clinical trials. Dabigatran and rivaroxaban were recently approved for prevention of cerebral embolism in patients with atrial fibrillation. The ad-vantages of dabigatran in comparison to warfarin are a lower rate of major bleedings with dabigatran 110mg bid, a better efficacy with dabigatran 150mg bid, no clinically relevant interactions with other drugs and no need for routine coagulation monitoring. The disadvantages are the absence of antidote and the absence of routine laboratory tests for precise mea-surements of anticoagulant effect of direct thrombin/ factor Xa inhibitors. This review will focus on throm-bin and factor Xa inhibitors, which are new and promising oral anticoagulants for the prevention of cerebral embolism. We will discuss their pharmacol-ogical and clinical properties and provide the most recent updates on their clinical trials.展开更多
The title compound （zifaxaban 2, C20HI6C1N3O4S, Mr = 429.87） was synthesized and its crystal structure was determined by single-crystal X-ray diffraction. Zifaxaban crystallizes in monoclinic, space group P21 with a...The title compound （zifaxaban 2, C20HI6C1N3O4S, Mr = 429.87） was synthesized and its crystal structure was determined by single-crystal X-ray diffraction. Zifaxaban crystallizes in monoclinic, space group P21 with a = 5.7900（12）, b = 13.086（3）, c = 12.889（3） A, β= 100.86（3）°, V = 959.1（3） ）k3, Z = 2, Dc= 1.489 g/cm3, F（000） = 444,μ= 0.342 mm-l, the final R = 0.0320 and wR = 0.0640 for 2717 observed reflections （I 〉 20（I）. The absolute configuration of the stereogenic center in the title compound was confirmed to be S by single-crystal X-ray diffraction. Four existing intermolecular hydrogen bonds help to stabilize the lattice and the molecule in the lattice to adopt an L-shape conformation. Zifaxaban was slightly more active than rivaroxaban 1 in in vitro assay against human FXa and therefore is promising as a drug candidate.展开更多
目的:评价Xa因子(FXa)抑制剂对急性冠脉综合征(ACS)的疗效及安全性。方法:计算机检索Cochrane Central Register of Controlled Trials、MEDLINE、EMbase、万方数据、中国知网数据库、中国生物医学文献数据库及维普数据库从建库至今有关...目的:评价Xa因子(FXa)抑制剂对急性冠脉综合征(ACS)的疗效及安全性。方法:计算机检索Cochrane Central Register of Controlled Trials、MEDLINE、EMbase、万方数据、中国知网数据库、中国生物医学文献数据库及维普数据库从建库至今有关FXa抑制剂对ACS患者疗效及安全性的临床随机对照试验(RCT)。由3名研究者进行文献提取和质量评价,对符合纳入标准的研究采用Review 5.1软件进行偏倚定性和Meta分析。结果:共纳入6篇RCT,均采用随机、双盲、安慰剂对照组,且数据完整,非选择性结果报道为低偏倚风险。Meta分析结果显示,低、中、高剂量FXa抑制剂均不能降低ACS患者全因死亡风险[RR=0.92,95%CI(0.80,1.07);RR=0.95,95%CI(0.48,1.87);RR=0.97,95%CI(0.38,2.52)];仅低剂量FXa抑制剂可以降低ACS患者再发心肌梗死风险[RR=0.87,95%CI(0.77,0.98)];FXa抑制剂不能明显降低ACS患者缺血性卒中风险[RR=0.98,95%CI(0.74,1.31)];低、中、高剂量FXa抑制剂均可增加ACS患者主要出血事件风险[RR=2.31,95%CI(1.66,3.21);RR=6.69,95%CI(2.73,16.43);RR=6.23,95%CI(2.75,14.14)]。结论:低剂量FXa抑制剂治疗ACS患者可以降低再发心肌梗死风险;FXa联合抗血小板药物治疗ACS对降低患者全因死亡、缺血性卒中和主要出血事件风险与既往抗血小板治疗比较并无明显优势。展开更多
基金financial supports of the National Natural Science Foundation of China (22078041, 22278053,22208042)Dalian High-level Talents Innovation Support Program (2023RQ059)“the Fundamental Research Funds for the Central Universities (DUT20JC41, DUT22YG218)”。
文摘Small-molecule drugs are essential for maintaining human health. The objective of this study is to identify a molecule that can inhibit the Factor Xa protein and be easily procured. An optimization-based de novo drug design framework, Drug CAMD, that integrates a deep learning model with a mixed-integer nonlinear programming model is used for designing drug candidates. Within this framework, a virtual chemical library is specifically tailored to inhibit Factor Xa. To further filter and narrow down the lead compounds from the designed compounds, comprehensive approaches involving molecular docking,binding pose metadynamics(BPMD), binding free energy calculations, and enzyme activity inhibition analysis are utilized. To maximize efficiency in terms of time and resources, molecules for in vitro activity testing are initially selected from commercially available portions of customized virtual chemical libraries. In vitro studies assessing inhibitor activities have confirmed that the compound EN300-331859shows potential Factor Xa inhibition, with an IC_(50)value of 34.57 μmol·L^(-1). Through in silico molecular docking and BPMD, the most plausible binding pose for the EN300-331859-Factor Xa complex are identified. The estimated binding free energy values correlate well with the results obtained from biological assays. Consequently, EN300-331859 is identified as a novel and effective sub-micromolar inhibitor of Factor Xa.
文摘Vitamin K antagonists, such as warfarin and phen-procoumon, are the first-line oral anticoagulants for primary and secondary prevention of cerebral embo-lism in patients with atrial fibrillation. Although vitamin K antagonists can significantly decrease the risk of stroke, their use is limited by several important drawbacks, such as a narrow therapeutic window, the risk of intracranial and gastrointestinal bleeding, interactions with a number of drugs and nutrients, and the need for regular laboratory tests for therapy adjustment. Currently, new oral anticoagulants, such as direct thrombin inhibitors (e.g., dabigatran) and direct factor Xa inhibitors (e.g., apixaban, rivaroxaban), are being developed and tested in clinical trials. Dabigatran and rivaroxaban were recently approved for prevention of cerebral embolism in patients with atrial fibrillation. The ad-vantages of dabigatran in comparison to warfarin are a lower rate of major bleedings with dabigatran 110mg bid, a better efficacy with dabigatran 150mg bid, no clinically relevant interactions with other drugs and no need for routine coagulation monitoring. The disadvantages are the absence of antidote and the absence of routine laboratory tests for precise mea-surements of anticoagulant effect of direct thrombin/ factor Xa inhibitors. This review will focus on throm-bin and factor Xa inhibitors, which are new and promising oral anticoagulants for the prevention of cerebral embolism. We will discuss their pharmacol-ogical and clinical properties and provide the most recent updates on their clinical trials.
基金Supported by Key Projects of Tianjin Science and Technology Support Plan(12ZCZDSY01100)
文摘The title compound （zifaxaban 2, C20HI6C1N3O4S, Mr = 429.87） was synthesized and its crystal structure was determined by single-crystal X-ray diffraction. Zifaxaban crystallizes in monoclinic, space group P21 with a = 5.7900（12）, b = 13.086（3）, c = 12.889（3） A, β= 100.86（3）°, V = 959.1（3） ）k3, Z = 2, Dc= 1.489 g/cm3, F（000） = 444,μ= 0.342 mm-l, the final R = 0.0320 and wR = 0.0640 for 2717 observed reflections （I 〉 20（I）. The absolute configuration of the stereogenic center in the title compound was confirmed to be S by single-crystal X-ray diffraction. Four existing intermolecular hydrogen bonds help to stabilize the lattice and the molecule in the lattice to adopt an L-shape conformation. Zifaxaban was slightly more active than rivaroxaban 1 in in vitro assay against human FXa and therefore is promising as a drug candidate.
文摘目的:评价Xa因子(FXa)抑制剂对急性冠脉综合征(ACS)的疗效及安全性。方法:计算机检索Cochrane Central Register of Controlled Trials、MEDLINE、EMbase、万方数据、中国知网数据库、中国生物医学文献数据库及维普数据库从建库至今有关FXa抑制剂对ACS患者疗效及安全性的临床随机对照试验(RCT)。由3名研究者进行文献提取和质量评价,对符合纳入标准的研究采用Review 5.1软件进行偏倚定性和Meta分析。结果:共纳入6篇RCT,均采用随机、双盲、安慰剂对照组,且数据完整,非选择性结果报道为低偏倚风险。Meta分析结果显示,低、中、高剂量FXa抑制剂均不能降低ACS患者全因死亡风险[RR=0.92,95%CI(0.80,1.07);RR=0.95,95%CI(0.48,1.87);RR=0.97,95%CI(0.38,2.52)];仅低剂量FXa抑制剂可以降低ACS患者再发心肌梗死风险[RR=0.87,95%CI(0.77,0.98)];FXa抑制剂不能明显降低ACS患者缺血性卒中风险[RR=0.98,95%CI(0.74,1.31)];低、中、高剂量FXa抑制剂均可增加ACS患者主要出血事件风险[RR=2.31,95%CI(1.66,3.21);RR=6.69,95%CI(2.73,16.43);RR=6.23,95%CI(2.75,14.14)]。结论:低剂量FXa抑制剂治疗ACS患者可以降低再发心肌梗死风险;FXa联合抗血小板药物治疗ACS对降低患者全因死亡、缺血性卒中和主要出血事件风险与既往抗血小板治疗比较并无明显优势。
