新型美普他酚类治疗AD的多靶向配体的设计、合成和生物活性
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摘要
阿尔茨海默病(Alzheimer's Disease,AD)属严重威胁老年人生命健康的神经系统退行性疾病。随着发病机理和致病基因的深入认识,从早期的以改善认知能力为主的“治标”药物转为阻止或逆转AD病程发展为目的的疾病修正类药物研究。同时,由于AD的多因子发病机制和复杂的病理生化改变,AD治疗方案开始向多途径、全方位发展;利用单一配体药物,同时作用AD的两个或更多个靶点的多靶向配体研究成为目前的热点。我们课题组自主开发的左旋美普他酚衍生物XQ509,具有抑制AChE(IC_(50)=3.9 nM)、抑制β-淀粉样蛋白(Aβ)聚集(IC_(50)=16.6μM)和抗炎(优于对照药布洛芬)的多重治疗AD作用;细胞和急性毒性极小(LD_(50)=313mg/kg),是一个很好的侯选药物,也是本论文的研究基础和立题依据。
论文从左旋美普他酚衍生物与TcAChE之间作用模式的研究出发,利用来源于相应的复合物晶体结构中的已知配体评价了FlexX、GOLD和MVD对接方法对AChE体系的可靠性,以及不同因素对结果的影响,最终建立起一种可靠的、适用于AChE抑制剂结合模式研究的MVD分子对接算法。利用此方法,对本课题组己合成的11个美普他酚双配体进行分子对接验证,三个打分函数值与实测活性均表现良好的相关性(最优r=0.948),证明了该方法的可靠性。我们还探讨了左旋美普他酚与TcAChE可能的结合模式,它能较好的解释美普他酚左旋体和右旋体药理活性的差异,并被我们最近得到的XQ509与TcAChE复合物的单晶X衍射结果确证。本研究结果为美普他酚双配基系列的设计提供了依据和参考。
根据基于性质的药物设计原理,良好的ADME/T性质与较强的生物学活性是上市药物必须同时具备的特征。XQ509具有有效的多重作用和极低的毒性,但它的脂溶性太大,溶解度差,不利于体内的吸收,为降低脂溶性,我们在XQ509的结构中引入亲水性片段,以改善其药代动力学性质。设计了结构多样的117个新化合物(连接链长为间隔8-11个原子距离),利用分子对接方法预测其活性;再通过ADME/T预测算法,淘汰类药性差的化合物。最终选定相对活性好,成药潜力大的5个化合物进行优先合成和药理研究。药理初筛显示,化合物ZQ103和ZQ105显示很好的AChE抑制活性。ZQ103的AChE抑制活性与XQ509相当;而它的类药性明显优于XQ509,更具有开发潜力。
另外,在分子对接研究中,我们发现先导化合物XQ509的对映体(药理编号ZQ100)有明显的预测活性,这引起了我们的关注,对其进行了合成和药理初筛,结果表明ZQ100也有较好的AChE抑制活性,IC_(50)为193 nM,甚至比上市药物利斯的明高28倍。我们利用新解析的XQ509与TcAChE复合物的晶体结构作进一步的分子对接研究,探讨了化合物ZQ100与AChE催化位点和PAS的作用模式。
研究表明金属离子具有促进纤维产生和沉积的作用,同时金属离子异常与加剧氧化损害有直接联系。调节脑内的金属平衡已成为AD的一有效治疗策略。我们在XQ509的中间连接链部分引入金属离子螯合剂的药效基团,使其在保持原有的多重作用外,还能具有协同的金属离子螯合作用。设计了系列新化合物并进行虚拟筛选,选择了其中的2个化合物进行优先合成。初步药理结果显示化合物ZQ106和ZQ107具有金属离子螯合作用的同时保留了AChE抑制活性,它同时满足了类药性要求,值得继续进行抗AB聚集和抗炎活性研究,希望能作为治疗AD的多靶向配体开发。
在神经退行性疾病中的活性氧分子(ROS)的危害性类似于感染性疾病中的微生物,细胞内氧异常发生在AD病程的早期,可能是AD病程发展的最主要诱因之一。几项临床研究己证实了抗氧剂治疗AD等神经退行性疾病的有效性。我们运用多靶点治疗策略,采用药效团的拼合原理,将左旋美普他酚分别与具有抗氧作用的硫辛酸和褪黑素分子拼合,希望获得具有AChE抑制、抗Aβ聚集、抗炎和抗氧化多重作用的候选药物分子,达到有效治疗AD的目的。共设计了47个新化合物并进行虚拟筛选,选择了其中的4个化合物进行优先合成。其中化合物ZQ211和ZQ309对AChE的IC_(50)分别为1.821μM和1.261μM,优于上市药物利斯的明(IC_(50)=5.5μM),它们的抗氧活性测试正在进行中。
全文共涉及40个化合物的合成和结构确证,未见报道的新化合物26个,进行药理筛选的化合物12个。
为减少合成化合物的数量,提高命中率,运用计算机辅助设计和经典的药物化学相结合的方法,对侯选药XQ509进行结构修饰和优化,是本论文的特色。最终成功筛选出活性高且类药性好的化合物ZQ103;发现了具有金属离子螯合作用且保留AChE抑制活性的化合物ZQ106和ZQ107,其预期的抗Aβ聚集和抗炎活性还有待研究。这三个化合物值得进一步研究,是本论文的创新成果。
Alzheimer's disease(AD),which is a kind of neurodegenerative disease,is becoming a serious threat to life expectancy for elderly people.With more understanding of the pathogenesis of AD,AD drug development has gradually shifted from the early palliative treatments mainly based on alleviating the cognitive deficit, to today's disease-modifying drugs on preventing or reversing the,course of AD.At the same time,as a result of the multifactorial pathogenesis and complicated pathological changes,treatments for AD have shown multi-ways and omni-direction. A hot area of study is to employ one compound to hit the multiple targets,which can be termed as multi-target-directed ligands.
In our previous study,we have developed(-)-meptazinol(MEP) derivative XQ509 as a good AD candidate,which has multiple functions,i.e.,inhibiting of AChE(IC_(50) =3.9 nM),preventing AChE-induced Aβaggregation(IC_(50)=16.6μM) and anti-inflammatory activities(better than the control drug ibuprofen);Additionally,its cytotoxicity and acute toxicity is very low(LD_(50)=313 mg/kg).Further study is ongoing.
In this thesis,starting with investigations on the action mechanism of(-)-MEP derivatives on TcAChE using the known crystal structures of TcAChE-ligand complexes,We evaluated the reliabilities of FlexX,GOLD and MVD molecular docking methods on AChE system,and different factors that may affect the result. Finally,we set up a reliable MVD molecular docking that fit for ACHE.11 bis-(-)-nor-MEP ligands in our group were verified efficiently by this new method. Three docking scores and their experimental activities showed good correlation(up to r=0.948),which proved that the method was reliable.We also explored the possible binding mode of(-)-MEP on TcAChE,which could explain the pharmacological difference between(+)- and(-)-meptazinol enantiomers.The results were verified by X-Ray crystal diffraction of XQ509 and TcAChE complex,which was important for structural optimization of XQ509.
An ideal marketed drug should simultaneously have good ADME/T(absorption, distribution,metabolism,excretion/toxicity) nature and strong biological activity. XQ509 is multipotent and low toxic,but it is not conducive to absorption and distribution in vivo due to its high lipophilicity and low solubility."Property-based drug design" strategy was applied aiming to reduce lipophilicity by introducing hydrophilic fragments into XQ509.Six series of totally 117 compounds were designed,and their activities were virtually screened using molecular docking method. We also predicted their ADME/T properties,and eliminate those with bad drug-like properties.Finally,5 compounds were chosen for synthesis and pharmacological study.Of those compounds,ZQ103 showed excellent AChE inhibitory activity, similar to lead compound XQ509,and its "drug-like" was significantly better than XQ509,which indicated that ZQ103 is a promising drug candidate.
In addition,we found that enantiomer of XQ509(pharmacological code ZQ100) also had significant predicted activity in molecular docking studies,which aroused our attention.ZQ100 was synthesized,and its AChE inhibitory activity(IC_(50)=193 nM) was 28 times more potent than a marketed drug rivastigmine.Molecular modeling of ZQ100 was performed to elucidate its binding pose and interactions with the active sites of the enzyme.
It is evident that metal ions can accelerate the production and aggregation of Aβ, and abnormal metal ion would promote oxidative damage.Therefore,adjustment of metal ion balance is an effective way to treat AD.In my design,metal chelation pharmacophores were introduced into the middle chain of XQ509,keeping its multifunctions and with a synergistic metal-chelation effect.A few new compounds were designed and screened.2 of them were synthesized initially.Physiological study showed that compounds ZQ106 and ZQ107 keep AChE inhibition activity and metal chelation property.They are also satisfied with drug-like properties and further studies are ongoing.
The damage of reactive oxygen species(ROS) in neurodegenerative diseases is similar to that of microorganism in infectious diseases.The abnormal activity of oxygen inside cells occurs in the beginning of AD,and most probably is what induces the progression of AD.Several clinical studies verified the efficiency of antioxidant on neurodegenerative diseases,including AD.We applied multi-target strategy,with the combination of pharmacophores.(-)-MEP was combined to antioxidants thioctic acid and melatonin,wishing to get drug candidates with AChE inhibition activity, anti-Aβaggregation,and antioxidant activity,to achieve efficient AD therapy.In this study,47 new compounds were designed and virtual screened,of which,4 compounds were chosen for synthesis initially.Compounds ZQ211 and ZQ309 showed IC_(50) of 1.821μM and 1.261μM respectively,which are better than marketed drug rivastigmine (IC_(50)=5.5μM).Their pharmacological studies in antioxidative activity are currently underways.
Especially noteworthy,to reduce the number of synthesized compounds and improve efficiency,we use the combination of computer aided drug design and traditional medicinal chemistry to design and optimize the structure of candidate XQ509,which is the special feature of this thesis.At last,we successfully screened out the compound ZQ103 with good activity and drug-like properties,and the compounds ZQ106 and ZQ107 with good AChE inhibition activities and metal chelation properties.
All together,40 compounds were reported in this thesis,including their synthesis and structure verification;Of them,26 are new compounds,and 12 compounds went to pharmacological screening.
论文从左旋美普他酚衍生物与TcAChE之间作用模式的研究出发,利用来源于相应的复合物晶体结构中的已知配体评价了FlexX、GOLD和MVD对接方法对AChE体系的可靠性,以及不同因素对结果的影响,最终建立起一种可靠的、适用于AChE抑制剂结合模式研究的MVD分子对接算法。利用此方法,对本课题组己合成的11个美普他酚双配体进行分子对接验证,三个打分函数值与实测活性均表现良好的相关性(最优r=0.948),证明了该方法的可靠性。我们还探讨了左旋美普他酚与TcAChE可能的结合模式,它能较好的解释美普他酚左旋体和右旋体药理活性的差异,并被我们最近得到的XQ509与TcAChE复合物的单晶X衍射结果确证。本研究结果为美普他酚双配基系列的设计提供了依据和参考。
根据基于性质的药物设计原理,良好的ADME/T性质与较强的生物学活性是上市药物必须同时具备的特征。XQ509具有有效的多重作用和极低的毒性,但它的脂溶性太大,溶解度差,不利于体内的吸收,为降低脂溶性,我们在XQ509的结构中引入亲水性片段,以改善其药代动力学性质。设计了结构多样的117个新化合物(连接链长为间隔8-11个原子距离),利用分子对接方法预测其活性;再通过ADME/T预测算法,淘汰类药性差的化合物。最终选定相对活性好,成药潜力大的5个化合物进行优先合成和药理研究。药理初筛显示,化合物ZQ103和ZQ105显示很好的AChE抑制活性。ZQ103的AChE抑制活性与XQ509相当;而它的类药性明显优于XQ509,更具有开发潜力。
另外,在分子对接研究中,我们发现先导化合物XQ509的对映体(药理编号ZQ100)有明显的预测活性,这引起了我们的关注,对其进行了合成和药理初筛,结果表明ZQ100也有较好的AChE抑制活性,IC_(50)为193 nM,甚至比上市药物利斯的明高28倍。我们利用新解析的XQ509与TcAChE复合物的晶体结构作进一步的分子对接研究,探讨了化合物ZQ100与AChE催化位点和PAS的作用模式。
研究表明金属离子具有促进纤维产生和沉积的作用,同时金属离子异常与加剧氧化损害有直接联系。调节脑内的金属平衡已成为AD的一有效治疗策略。我们在XQ509的中间连接链部分引入金属离子螯合剂的药效基团,使其在保持原有的多重作用外,还能具有协同的金属离子螯合作用。设计了系列新化合物并进行虚拟筛选,选择了其中的2个化合物进行优先合成。初步药理结果显示化合物ZQ106和ZQ107具有金属离子螯合作用的同时保留了AChE抑制活性,它同时满足了类药性要求,值得继续进行抗AB聚集和抗炎活性研究,希望能作为治疗AD的多靶向配体开发。
在神经退行性疾病中的活性氧分子(ROS)的危害性类似于感染性疾病中的微生物,细胞内氧异常发生在AD病程的早期,可能是AD病程发展的最主要诱因之一。几项临床研究己证实了抗氧剂治疗AD等神经退行性疾病的有效性。我们运用多靶点治疗策略,采用药效团的拼合原理,将左旋美普他酚分别与具有抗氧作用的硫辛酸和褪黑素分子拼合,希望获得具有AChE抑制、抗Aβ聚集、抗炎和抗氧化多重作用的候选药物分子,达到有效治疗AD的目的。共设计了47个新化合物并进行虚拟筛选,选择了其中的4个化合物进行优先合成。其中化合物ZQ211和ZQ309对AChE的IC_(50)分别为1.821μM和1.261μM,优于上市药物利斯的明(IC_(50)=5.5μM),它们的抗氧活性测试正在进行中。
全文共涉及40个化合物的合成和结构确证,未见报道的新化合物26个,进行药理筛选的化合物12个。
为减少合成化合物的数量,提高命中率,运用计算机辅助设计和经典的药物化学相结合的方法,对侯选药XQ509进行结构修饰和优化,是本论文的特色。最终成功筛选出活性高且类药性好的化合物ZQ103;发现了具有金属离子螯合作用且保留AChE抑制活性的化合物ZQ106和ZQ107,其预期的抗Aβ聚集和抗炎活性还有待研究。这三个化合物值得进一步研究,是本论文的创新成果。
Alzheimer's disease(AD),which is a kind of neurodegenerative disease,is becoming a serious threat to life expectancy for elderly people.With more understanding of the pathogenesis of AD,AD drug development has gradually shifted from the early palliative treatments mainly based on alleviating the cognitive deficit, to today's disease-modifying drugs on preventing or reversing the,course of AD.At the same time,as a result of the multifactorial pathogenesis and complicated pathological changes,treatments for AD have shown multi-ways and omni-direction. A hot area of study is to employ one compound to hit the multiple targets,which can be termed as multi-target-directed ligands.
In our previous study,we have developed(-)-meptazinol(MEP) derivative XQ509 as a good AD candidate,which has multiple functions,i.e.,inhibiting of AChE(IC_(50) =3.9 nM),preventing AChE-induced Aβaggregation(IC_(50)=16.6μM) and anti-inflammatory activities(better than the control drug ibuprofen);Additionally,its cytotoxicity and acute toxicity is very low(LD_(50)=313 mg/kg).Further study is ongoing.
In this thesis,starting with investigations on the action mechanism of(-)-MEP derivatives on TcAChE using the known crystal structures of TcAChE-ligand complexes,We evaluated the reliabilities of FlexX,GOLD and MVD molecular docking methods on AChE system,and different factors that may affect the result. Finally,we set up a reliable MVD molecular docking that fit for ACHE.11 bis-(-)-nor-MEP ligands in our group were verified efficiently by this new method. Three docking scores and their experimental activities showed good correlation(up to r=0.948),which proved that the method was reliable.We also explored the possible binding mode of(-)-MEP on TcAChE,which could explain the pharmacological difference between(+)- and(-)-meptazinol enantiomers.The results were verified by X-Ray crystal diffraction of XQ509 and TcAChE complex,which was important for structural optimization of XQ509.
An ideal marketed drug should simultaneously have good ADME/T(absorption, distribution,metabolism,excretion/toxicity) nature and strong biological activity. XQ509 is multipotent and low toxic,but it is not conducive to absorption and distribution in vivo due to its high lipophilicity and low solubility."Property-based drug design" strategy was applied aiming to reduce lipophilicity by introducing hydrophilic fragments into XQ509.Six series of totally 117 compounds were designed,and their activities were virtually screened using molecular docking method. We also predicted their ADME/T properties,and eliminate those with bad drug-like properties.Finally,5 compounds were chosen for synthesis and pharmacological study.Of those compounds,ZQ103 showed excellent AChE inhibitory activity, similar to lead compound XQ509,and its "drug-like" was significantly better than XQ509,which indicated that ZQ103 is a promising drug candidate.
In addition,we found that enantiomer of XQ509(pharmacological code ZQ100) also had significant predicted activity in molecular docking studies,which aroused our attention.ZQ100 was synthesized,and its AChE inhibitory activity(IC_(50)=193 nM) was 28 times more potent than a marketed drug rivastigmine.Molecular modeling of ZQ100 was performed to elucidate its binding pose and interactions with the active sites of the enzyme.
It is evident that metal ions can accelerate the production and aggregation of Aβ, and abnormal metal ion would promote oxidative damage.Therefore,adjustment of metal ion balance is an effective way to treat AD.In my design,metal chelation pharmacophores were introduced into the middle chain of XQ509,keeping its multifunctions and with a synergistic metal-chelation effect.A few new compounds were designed and screened.2 of them were synthesized initially.Physiological study showed that compounds ZQ106 and ZQ107 keep AChE inhibition activity and metal chelation property.They are also satisfied with drug-like properties and further studies are ongoing.
The damage of reactive oxygen species(ROS) in neurodegenerative diseases is similar to that of microorganism in infectious diseases.The abnormal activity of oxygen inside cells occurs in the beginning of AD,and most probably is what induces the progression of AD.Several clinical studies verified the efficiency of antioxidant on neurodegenerative diseases,including AD.We applied multi-target strategy,with the combination of pharmacophores.(-)-MEP was combined to antioxidants thioctic acid and melatonin,wishing to get drug candidates with AChE inhibition activity, anti-Aβaggregation,and antioxidant activity,to achieve efficient AD therapy.In this study,47 new compounds were designed and virtual screened,of which,4 compounds were chosen for synthesis initially.Compounds ZQ211 and ZQ309 showed IC_(50) of 1.821μM and 1.261μM respectively,which are better than marketed drug rivastigmine (IC_(50)=5.5μM).Their pharmacological studies in antioxidative activity are currently underways.
Especially noteworthy,to reduce the number of synthesized compounds and improve efficiency,we use the combination of computer aided drug design and traditional medicinal chemistry to design and optimize the structure of candidate XQ509,which is the special feature of this thesis.At last,we successfully screened out the compound ZQ103 with good activity and drug-like properties,and the compounds ZQ106 and ZQ107 with good AChE inhibition activities and metal chelation properties.
All together,40 compounds were reported in this thesis,including their synthesis and structure verification;Of them,26 are new compounds,and 12 compounds went to pharmacological screening.
引文
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