HIV-1抑制剂的研究
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摘要
二芳基嘧啶类化合物(Diarylpyrimidines, DAPY)是一类重要非核苷类逆转录酶抑制剂(NNRTIs),因其对诸多单突变和双突变耐药病毒株显示出很强抑制活性且具有较小的毒副作用而倍受关注,其中代表性化合物Etravirine (TMC 125)于2008年被FDA批准上市,而新一代DAPY化合物Rilpivirine (TMC278)现处于三期临床正待被批准上市。本论文拟选取Rilpivirine和Etravirine为先导化合物,设计新型的DAPY类目标化合物。
首先,采用ONIOM2(B3LYP/6-31(d,p):PM3)计算Dapivirine (TMC 120)与HIV-1 RT的疏水性结合袋(NNIBP)各残基的结合能,结果表明Dapivirine与RT具有两大作用：1)与残基Tys181的π-π堆积作用；2)与残基Lys101形成双氢键。在此基础上,我们构建了DAPY类化合物对野生型和耐药型L100I,Y181C和Y188L的2D-QSAR模型。2D-QSAR模型提示一个具有良好活性并能有效抑制耐药病毒株的DAPY类化合物具有如下特征：1)由于C-O和C-N键的键长比较相近,故左边连接基原子最好为N或者O；2)左苯环上具有氰基官能团,能增强与残基Tyr181的π-π堆积作用,从而有效制耐药病毒株L100I和Y188L。
在2D-QSAR模型和分子对接模型的基础上,设计合成了75个新型的DAPY类目标化合物。抗HIV活性测试结果表明所设计的DAPY类目标化合物均具有很强的抑制活性,其中18个目标化合物抑制HIV-1野生型病毒株活性小于10纳摩尔,其中9个目标化合物抗HIV-1野生型病毒株活性高于依法韦仑,而且所设计的目标化合物均具有较高的选择性指数,其中化合物1bk的SI值高达18万(EC50=1.6 nM)。通过测试抑制耐药病毒株RES056(103N+181C)揭示大部分萘环C-6位被氰基取代的目标化合物对耐药病毒株具有较强的抑制活性,有5个化合物的抑制活性优于依法韦仑(EC50=0.41μM),其中以化合物8bp和8bq抑制活性最高,EC50值分别为0.16μM和0.15μM,且其选择性指数SI大于2.5万。因此,这两个化合物分别命名为FDU-1r和FDU-1t作为临床侯选药物进行进一步的研究开发,以期开发出具有我国知识产权的抗艾滋病药物。
在DAPY类化合物TMC120与RT酶晶体结构中TMC120的药效构象基础上,建立目标化合物的3D-QSAR (CoMFA and CoMSIA)模型。从立体、静电和氢键作用等方面探讨了所设计目标化合物的构效关系,为下一步DAPY类化合物进一步设计奠定了理论基础。
第二部分内容是逆转录酶和整合酶双靶点抑制剂DABOs的分子设计,合成及抗HIV活性研究。基于整合酶抑制剂raltegravir的分子结构与非核苷类逆转录酶抑制剂DABOs的结构相似性,设计了一类新型的逆转录酶和整合酶双靶点抑制剂S-DABOs目标化合物,初步合成了4个双靶点抑制剂S-DABOs目标化合物15a-d和1个对比化合物19。
对所设计的逆转录酶和整合酶双靶点抑制剂S-DABO进行抗HIV-1和HIV-2细胞活性和毒性,以及抗RT酶水平活性测试,其测试活性结果表明所设计的双靶点抑制剂S-DABO抑制RT酶水平很弱,且细胞水平的活性测试表明双靶点抑制剂S-DABO不能有效抑制HIV-1及HIV-2复制。因此,对此类双靶点抑制剂S-DABO化合物还待进一步的设计研究。
Diarylpyrimidine derivatives (DAPYs), a novel class of non-nucleoside reverse transcriptase inhibitors (NNRTIs), have been attracted considerable attention due to their excellent potency against wild-type and mutant strains of HIV-1 reverse transcriptase (HIV-1 RT) relative to other NNRTIs. Etravirine (TMC125) has been approved by the FDA for treatment of patients infected with HIV-1 variants resistant to other antiretroviral drugs, and the second generation DAPY compound TMC278 (Rilpivirine) is currently in phase III clinical tials.
According to 2D-QSAR studied results and docking model of DAPY,75 newly naphthoxy (or 8-quinolinoxy) substituted DAPY, characterized by different substitution patterns on the pyrimidine and naphthalene ring, were designed and synthesized in a straightforward fashion by means of parallel synthesis in the first part. The antiviral and cytotoxicity evaluation indicated that most of the compounds displayed strong activity against wild-type HIV-1. Eighteen compounds displayed activity against HIV-1 wild-type lower than 10 nm, and the activity of nine compounds is higher than the second generation NNRTI efavirenz:8bf(0.003μM), 8bg(0.002μM),8bj(0.003μM),8bh(0.004μM),8bk(0.002μM),8bl(0.001μM), 8bn(0.002μM),8bo(0.002μM) and 8bv(0.003μM). The most active compound 8bk and 8bl with a cyano group at the position 6 on the naphthalene ring exhibited activity against HIV-1 wild-type at an EC50 of 1.6 nM and 1 nM, a selectivity index for the compound 8bk against wild-type is greater than 180 000 (the highest SI value among DAPY analogues). In order to investigate the anti drug resistant potency of these compounds, the activities against the double mutant strains 103N+181C were tested.5 compounds (8bk,8bn,8bp,8bq and 8bw) displayed activity against HIV-1 wild-type higher than efavirenz (EC50=0.41μM), the most active compounds 8bp and 8bq are selected and named as "FDU-lr" and "FDU-1t" for development as the candidate anti-HIV drugs.
On the basis of the test activities of 75 newly DAPY derivatives, the 3D-QSAR (CoMFA and CoMSIA) models were established. Based on the 3D QSAR models, the further SAR of these newly synthesized compounds were explored in the aspects of steric, electrostatic, hydrophobic, H-bond donor and acceptor fields. The conclusions summarized from these results will provide useful information for design new DAPYs as potent HIV-1 inhibitors.
In the second part, we designed and synthesized the dual inhibitors based on the integrase (IN) inhibitor raltegravir and the non-nucleoside RT inhibitors DABO (dihydroalkoxybenzyloxo-pyrimidines) according to the concept of designed multifunctional ligands (DML). Introduction of the hydroxy group at position C-5 on the pyrimidine ring of DABO compounds allows the incorporation of a second pharmacophore to generate acivity against IN. However, these dual inhibitors exhibited low activity against HIV-1 RT, and displayed no activity against HIV-1 wild type virus in MT-4 cells.
首先,采用ONIOM2(B3LYP/6-31(d,p):PM3)计算Dapivirine (TMC 120)与HIV-1 RT的疏水性结合袋(NNIBP)各残基的结合能,结果表明Dapivirine与RT具有两大作用：1)与残基Tys181的π-π堆积作用；2)与残基Lys101形成双氢键。在此基础上,我们构建了DAPY类化合物对野生型和耐药型L100I,Y181C和Y188L的2D-QSAR模型。2D-QSAR模型提示一个具有良好活性并能有效抑制耐药病毒株的DAPY类化合物具有如下特征：1)由于C-O和C-N键的键长比较相近,故左边连接基原子最好为N或者O；2)左苯环上具有氰基官能团,能增强与残基Tyr181的π-π堆积作用,从而有效制耐药病毒株L100I和Y188L。
在2D-QSAR模型和分子对接模型的基础上,设计合成了75个新型的DAPY类目标化合物。抗HIV活性测试结果表明所设计的DAPY类目标化合物均具有很强的抑制活性,其中18个目标化合物抑制HIV-1野生型病毒株活性小于10纳摩尔,其中9个目标化合物抗HIV-1野生型病毒株活性高于依法韦仑,而且所设计的目标化合物均具有较高的选择性指数,其中化合物1bk的SI值高达18万(EC50=1.6 nM)。通过测试抑制耐药病毒株RES056(103N+181C)揭示大部分萘环C-6位被氰基取代的目标化合物对耐药病毒株具有较强的抑制活性,有5个化合物的抑制活性优于依法韦仑(EC50=0.41μM),其中以化合物8bp和8bq抑制活性最高,EC50值分别为0.16μM和0.15μM,且其选择性指数SI大于2.5万。因此,这两个化合物分别命名为FDU-1r和FDU-1t作为临床侯选药物进行进一步的研究开发,以期开发出具有我国知识产权的抗艾滋病药物。
在DAPY类化合物TMC120与RT酶晶体结构中TMC120的药效构象基础上,建立目标化合物的3D-QSAR (CoMFA and CoMSIA)模型。从立体、静电和氢键作用等方面探讨了所设计目标化合物的构效关系,为下一步DAPY类化合物进一步设计奠定了理论基础。
第二部分内容是逆转录酶和整合酶双靶点抑制剂DABOs的分子设计,合成及抗HIV活性研究。基于整合酶抑制剂raltegravir的分子结构与非核苷类逆转录酶抑制剂DABOs的结构相似性,设计了一类新型的逆转录酶和整合酶双靶点抑制剂S-DABOs目标化合物,初步合成了4个双靶点抑制剂S-DABOs目标化合物15a-d和1个对比化合物19。
对所设计的逆转录酶和整合酶双靶点抑制剂S-DABO进行抗HIV-1和HIV-2细胞活性和毒性,以及抗RT酶水平活性测试,其测试活性结果表明所设计的双靶点抑制剂S-DABO抑制RT酶水平很弱,且细胞水平的活性测试表明双靶点抑制剂S-DABO不能有效抑制HIV-1及HIV-2复制。因此,对此类双靶点抑制剂S-DABO化合物还待进一步的设计研究。
Diarylpyrimidine derivatives (DAPYs), a novel class of non-nucleoside reverse transcriptase inhibitors (NNRTIs), have been attracted considerable attention due to their excellent potency against wild-type and mutant strains of HIV-1 reverse transcriptase (HIV-1 RT) relative to other NNRTIs. Etravirine (TMC125) has been approved by the FDA for treatment of patients infected with HIV-1 variants resistant to other antiretroviral drugs, and the second generation DAPY compound TMC278 (Rilpivirine) is currently in phase III clinical tials.
According to 2D-QSAR studied results and docking model of DAPY,75 newly naphthoxy (or 8-quinolinoxy) substituted DAPY, characterized by different substitution patterns on the pyrimidine and naphthalene ring, were designed and synthesized in a straightforward fashion by means of parallel synthesis in the first part. The antiviral and cytotoxicity evaluation indicated that most of the compounds displayed strong activity against wild-type HIV-1. Eighteen compounds displayed activity against HIV-1 wild-type lower than 10 nm, and the activity of nine compounds is higher than the second generation NNRTI efavirenz:8bf(0.003μM), 8bg(0.002μM),8bj(0.003μM),8bh(0.004μM),8bk(0.002μM),8bl(0.001μM), 8bn(0.002μM),8bo(0.002μM) and 8bv(0.003μM). The most active compound 8bk and 8bl with a cyano group at the position 6 on the naphthalene ring exhibited activity against HIV-1 wild-type at an EC50 of 1.6 nM and 1 nM, a selectivity index for the compound 8bk against wild-type is greater than 180 000 (the highest SI value among DAPY analogues). In order to investigate the anti drug resistant potency of these compounds, the activities against the double mutant strains 103N+181C were tested.5 compounds (8bk,8bn,8bp,8bq and 8bw) displayed activity against HIV-1 wild-type higher than efavirenz (EC50=0.41μM), the most active compounds 8bp and 8bq are selected and named as "FDU-lr" and "FDU-1t" for development as the candidate anti-HIV drugs.
On the basis of the test activities of 75 newly DAPY derivatives, the 3D-QSAR (CoMFA and CoMSIA) models were established. Based on the 3D QSAR models, the further SAR of these newly synthesized compounds were explored in the aspects of steric, electrostatic, hydrophobic, H-bond donor and acceptor fields. The conclusions summarized from these results will provide useful information for design new DAPYs as potent HIV-1 inhibitors.
In the second part, we designed and synthesized the dual inhibitors based on the integrase (IN) inhibitor raltegravir and the non-nucleoside RT inhibitors DABO (dihydroalkoxybenzyloxo-pyrimidines) according to the concept of designed multifunctional ligands (DML). Introduction of the hydroxy group at position C-5 on the pyrimidine ring of DABO compounds allows the incorporation of a second pharmacophore to generate acivity against IN. However, these dual inhibitors exhibited low activity against HIV-1 RT, and displayed no activity against HIV-1 wild type virus in MT-4 cells.
引文
TMC128与RT酶的晶体结构研究表明,TMC128类化合物也以“U”型构象与HIV-1 RT酶结合(Fig1-11),与TMC120类化合物不同的是,TMC128的氰乙烯基与非突变残基Trp229有很强的“π-π”堆积作用,从而使该类化合物对耐药病毒株有强的抑制活性。
Janssen公司所开发的DAPY类化合物已成为一类重要的非核苷类逆转录酶抑制剂(NNRTIs)。由于此类化合物具有对临床单突变和双突变的耐药病毒株显示出强的抑制作用,且已有一个代表性化合物TMC125于2008年被美国FDA批准上市,同时第二代DAPY类化合物的TMC278已处于临床三期正待批准上市。因此,此类化合物在抗HIV-1的药物研发中占有极其重要地位。在前期工作中,课题上在DATA的基础上设计开发出了Naph-DATA类化合物,将左翼用共轭体系更大的萘环替代,所设计的化合物已表现强的抗HIV活性。为更好地了解DAPY类化合物的构效关系,研发出高效、低毒,并具有抗耐药性的HIV-1抑制剂,本论文同样对DAPY类化合物“左翼”交换为共轭体系更大的萘环。
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[29]Dragon Evaluation Version 5.4,2006,. 和量子理论计算均表明萘环6位引入氰基能增强抑制剂与NNIBP的疏水性残基的“π,π”作用,CoMSIA的简单静电场计算无法表达此作用(这种“π,π”作用须采用从头计算才能得知)。
Naph-DAPY类化合物的抗HIV-1活性受取代基体积、电性和氢键受体场的影响。经CoMSIA分析使得我们对其构效关系作出了合理的解释,并为进一步提高化合物的活性指明了方向。
1)嘧啶环C-4位芳环取代基对目标化合物的抗HIV-1活性具有显著的影响,2-萘氧基取代的DAPY类化合物的抗HIV活性最强。
2)嘧啶环C-4位萘环C-1位引入取代基有利于化合物的抗HIV-1活性。
3)嘧啶环C-4位萘环C-6位引入氰基有利于化合物的抗HIV-1活性。
4)嘧啶环C-5位和C-6位无取代基有利于化合物的抗HIV-1活性。
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19 in MT-4 CellsaΟ15a-15d 19
15a Ph 95.09 36.0 36.0 36.0 <1
15b 4-Cl-Ph 113.1 163.5 163.5 163.5 <1
15c 4-Br-Ph >200 175.0 175.0 175.0 <1
15d Naph 165.9
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Janssen公司所开发的DAPY类化合物已成为一类重要的非核苷类逆转录酶抑制剂(NNRTIs)。由于此类化合物具有对临床单突变和双突变的耐药病毒株显示出强的抑制作用,且已有一个代表性化合物TMC125于2008年被美国FDA批准上市,同时第二代DAPY类化合物的TMC278已处于临床三期正待批准上市。因此,此类化合物在抗HIV-1的药物研发中占有极其重要地位。在前期工作中,课题上在DATA的基础上设计开发出了Naph-DATA类化合物,将左翼用共轭体系更大的萘环替代,所设计的化合物已表现强的抗HIV活性。为更好地了解DAPY类化合物的构效关系,研发出高效、低毒,并具有抗耐药性的HIV-1抑制剂,本论文同样对DAPY类化合物“左翼”交换为共轭体系更大的萘环。
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Naph-DAPY类化合物的抗HIV-1活性受取代基体积、电性和氢键受体场的影响。经CoMSIA分析使得我们对其构效关系作出了合理的解释,并为进一步提高化合物的活性指明了方向。
1)嘧啶环C-4位芳环取代基对目标化合物的抗HIV-1活性具有显著的影响,2-萘氧基取代的DAPY类化合物的抗HIV活性最强。
2)嘧啶环C-4位萘环C-1位引入取代基有利于化合物的抗HIV-1活性。
3)嘧啶环C-4位萘环C-6位引入氰基有利于化合物的抗HIV-1活性。
4)嘧啶环C-5位和C-6位无取代基有利于化合物的抗HIV-1活性。
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19 in MT-4 CellsaΟ15a-15d 19
15a Ph 95.09 36.0 36.0 36.0 <1
15b 4-Cl-Ph 113.1 163.5 163.5 163.5 <1
15c 4-Br-Ph >200 175.0 175.0 175.0 <1
15d Naph 165.9
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