Principal factors affecting anti-integrase strand transfer activities of 1-hydroxy-2-oxo-1 and 8-naphthyridine-3-carboxamides HIV integrase strand transfer inhibitors (INSTIs)

KANG Jiaxiong; LI Aixiu; JIN Yurui

PDF(1798 KB)

Medical Journal of the Chinese People Armed Police Forces ›› 2022, Vol. 33 ›› Issue (5) : 390-394.

Principal factors affecting anti-integrase strand transfer activities of 1-hydroxy-2-oxo-1 and 8-naphthyridine-3-carboxamides HIV integrase strand transfer inhibitors (INSTIs)

KANG Jiaxiong^1,2, LI Aixiu^2,3, JIN Yurui²

Author information +

History +

Abstract

Objective To explore the principal microstructural factors affecting the anti-integrase strand transfer (INST) activities of 1-hydroxy-2-oxo-1 and 8-naphthyridine-3-carboxamides HIV integrase strand transfer inhibitors (INSTIs). Methods Using genetic function approximation method, ten 2d-quantitative structure-activity relationship (2D-QSAR) models of 1-hydroxy-2-oxo-1 and 8-naphthyridine-3-carboxamides INSTIs were constructed, from which the optimal one was chosen and the primary microstructural factors affecting the anti-INST activities of the inhibitors were analyzed. Results The no-cross-validated value (R²) of the optimal 2D-QSAR model was 0.8555, the leave one out cross-validated value (Q²loo) was 0.7761, and the external cross-validated value (R²ext) was 0.94. These parameters indicated that the model constructed possessed fairly statistical significance and stability. Conclusions The anti-INST activities of the 1-hydroxy-2-oxo-1 and 8-naphthyridine-3-carboxamides INSTIs are mainly correlated with the descriptors of JX, Dipole_mag, Jurs_PNSA_1 and Strain_Energy, which provides theoretical basis for the further rational design of the inhibitors.

Key words

1-hydroxy-2-oxo-1,8-naphthyridine-3-carboxamide / human immunodeficiency virus / integrase strand transfer inhibitors / genetic function approximation / 2d-quantitative structure-activity relationship

Cite this article

EndNote

Ris (Procite)

Bibtex

Download Citations

KANG Jiaxiong, LI Aixiu, JIN Yurui. Principal factors affecting anti-integrase strand transfer activities of 1-hydroxy-2-oxo-1 and 8-naphthyridine-3-carboxamides HIV integrase strand transfer inhibitors (INSTIs)[J]. Medical Journal of the Chinese People Armed Police Forces. 2022, 33(5): 390-394

References

[1] 肖泽云, 李爱秀, 李凯, 等. 抗HIV中药复方的优选及其小分子数据库的构建和类药性分析[J]. 武警医学, 2019, 30(1): 46-50.
[2] 康家雄, 朱江, 李爱秀, 等. 化学合成类HIV整合酶和核糖核酸酶H双靶点抑制剂的研究进展[J]. 药学学报, 2019, 54(8): 1392-1401.
[3] Smith S J, Zhao X Z, Passos D O, et al. Integrase strand transfer inhibitors are effective anti-HIV drugs[J]. Viruses, 2021, 13(2): 205-232.
[4] Smith S J, Zhao X Z, Passos D O, et al. HIV-1 integrase inhibitors with modifications that affect their potencies against drug resistant integrase mutants[J]. ACS Infect Dis, 2021, 7(6): 1469-1482.
[5] Zhou J, Hao J, Peng L X, et al. Classification and design of HIV-1 integrase inhibitors based on machine learning[J]. Comput Math Methods Med, 2021, 2021(2): 1-11.
[6] Markham A. Bictegravir: first global approval[J]. Drugs, 2018, 78(5): 601-606.
[7] 陈本川. 人类免疫缺陷病毒整合酶链转移抑制新药-卡波拉韦及其复方长效注射液[J]. 医药导报, 2021, 358(8): 1148-1159.
[8] Smith S J, Zhao X Z, Burke T R, et al. Efficacies of cabotegravir and bictegravir against drug-resistant HIV-1 integrase mutants[J]. Retrovirology, 2018, 15(1): 37-54.
[9] Yang L L, Li Q, Zhou L B, et al. Meta-analysis and systematic review of the efficacy and resistance for human immunodeficiency virus type 1 integrase strand transfer inhibitors[J]. Int J Antimicrob Agents, 2019, 54(5): 547-555.
[10] Mbisa J L, Juan L, Peter K, et al. Surveillance of HIV-1 transmitted integrase strand transfer inhibitor resistance in the UK[J]. J Antimicrob Chemother, 2020, 75(11): 3311-3318.
[11] Zhao X Z, Smith S J, Métifiot M, et al. 4-Amino-1-hydroxy-2-oxo-1,8-naphthyridine-containing compounds having high potency against raltegravir-resistant integrase mutants of HIV-1[J]. J Med Chem, 2014, 57(12): 5190-5202.
[12] Zhao X Z, Smith S J, Métifiot M, et al. Bicyclic 1-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide-containing HIV-1 integrase inhibitors having high antiviral potency against cells harboring raltegravir-resistant integrase mutants[J]. J Med Chem, 2014, 57(4): 1573-1582.
[13] Zhao X Z, Smith S J, Maskell D P, et al. HIV-1 integrase strand transfer inhibitors with reduced susceptibility to drug resistant mutant integrases[J]. ACS Chem Biol, 2016, 4(11): 1074-1081.
[14] Zhao X Z, Smith S J, Maskell D P, et al. Structure-guided optimization of HIV integrase strand transfer inhibitors[J]. J Med Chem, 2017, 17(60): 7315-7332.
[15] 汪斌, 刘蒙蒙, 周朋朋, 等. 嘧啶衍生物类PI3K/mTOR双重抑制剂的3D-QSAR及分子对接研究[J].中国科学: 化学, 2017, 47(7): 865-875.
[16] 康家雄, 朱江, 李爱秀, 等. 喹诺酮酸类HIV-1整合酶链转移抑制剂的2D-QSAR研究[J]. 计算机与应用化学, 2019, 36(1): 24-34.
[17] 林峰, 付新梅, 王超, 等. 3C-like蛋白酶抑制剂的构效关系、分子对接和分子动力学[J]. 物理化学学报, 2016, 32(11): 2693-2708.
[18] 康家雄, 朱江, 李爱秀, 等. MKC-442及其类似物的二维定量构效关系[J]. 中国新药杂志, 2019, 28(23): 2885-2892.
[19] Fan T, Sun G, Zhao L, et al. QSAR and classification study on prediction of acute oral toxicity of N-nitroso compounds[J]. Int J Mol Sci, 2018, 19(10): 3015-3037.
[20] Roy P P, Paul S, Mitra I, et al. On two novel parameters for validation of predictive QSAR models[J]. Molecules, 2009, 14(5): 1660-1701.
[21] 孟繁宗, 王少坤. 烷基苯类化合物结构-热力学性质定量构效关系研究[J]. 化学通报, 2004, 14(5): 387-392.
[22] 孟繁宗, 苗深花. 烷基苯热力学性质与分子结构之间的关系研究[J]. 曲阜师范大学学报(自然科学版), 2004, 30(2): 69-73.
[23] 陈可先. 定量结构-活性关系(QSAR)在医药研究中的应用[D]. 杭州: 浙江工业大学, 2009.
[24] 李卫国, 邵家兴, 寇海波, 等. 材料高温力学性能理论表征方法研究进展[J]. 固体力学学报, 2017, 38(2): 4-34.
[25] 张英, 郭奇峰, 蔡美峰, 等. 硬岩脆性指标与弹性应变能关系初探[J]. 哈尔滨工业大学学报, 2019, 51(6): 85-94.
[26] 李祖光, 陈可先, 曹慧, 等. 新型-2-烷氧基-4(3H)-喹唑啉酮类杀菌剂的QSAR研究[J]. 农药, 2008, 47(5): 339-343.
[27] 丁俊杰, 丁晓琴, 赵立峰, 等. 新型三维氨基酸结构描述符的研究及其在多肽QSAR中的应用[J]. 药学学报, 2005, 40(4): 340-346.