Three Dimensional Quantitative Structure-activity Relationship of HEPT Analogues as HIV-1 Reverse Transcriptase Inhibitors

Abstract

Abstract: Hydroxyethoxy)methyl]-6-(phenylthio)-thymine(HEPT) and its analogues inhibit HIV-1 reverse transcriptase(RT) selectively. Aseries of HEPTanalogues were analyzed in order to disclose the relationship between their structure and the activity. Thirty two HIV-1RTinhibitors were investigated by means of comparative molecular field analysis(CoMFA). Based upon the active conformation extracted from the HEPT/HIV-1RTcomplex, all the inhibitors were aligned and minimized in energy. Three kinds of CoMFAmodels were established and evaluated. The model(Ⅰ)of steric and electrostatic effects on their activities showed a higher ability to explain and predict the activities of these selective HIV-1 inhibitors than other models, cross-validated R_CV²= 0.870, non-cross-validated R²= 0.986, F =294.546, standard error(SE)=0.146. The CoMFAmodel established by examining the steric and electrostatic effect on the structure without considering the effect of π value shows a very high ability to predict the biological activity for testing set compounds and training set compounds and offers an approach to design the new inhibitors. The CoMFAmodel revealed that the suitable length of the 1-side chain is crucial for the antiviral activity. And it also showed that the bulkier group in 5-position and the para-position of the 6-phenylthio group is also benefit for the enhancement of the antiviral activity.

Key words: HIV-1 reverse transcriptase inhibitors, HEPT analogues, CoMFA, 3D QSAR

CLC Number:

O626

TrendMD:

MENG Ge, HE Yan-Ping, CHEN Fen-Er . Three Dimensional Quantitative Structure-activity Relationship of HEPT Analogues as HIV-1 Reverse Transcriptase Inhibitors[J]. Chem. J. Chinese Universities, 2002, 23(7): 1304.

[1]	TANG Guanghui, ZHANG Ya, ZHANG Yuping, ZHOU Pengpeng, LIN Zhihua, WANG Yuanqiang. Molecular Docking, QSAR and Molecular Dynamics Simulation on Phosphorus Containing Pyrimidines as CDK9 Inhibitors^† [J]. Chem. J. Chinese Universities, 2017, 38(11): 2061.
[2]	LIU Benguo, LIU Jiangwei, LI Jiaqi, GENG Sheng, MO Haizhen, LIANG Guizhao. 3D-QSAR and Interaction Mechanism of Flavonoids s P-glycoprotein Inhibitors^† [J]. Chem. J. Chinese Universities, 2017, 38(1): 41.
[3]	WANG Meiyi, MA Yi, WANG Haiying, CAO Gang, LI Zhengming. Kinetics of the Chemical Hydrolysis and 3D-QSAR Study of 5-Substituted Benzenesulfonylurea Compounds^† [J]. Chem. J. Chinese Universities, 2016, 37(9): 1636.
[4]	MIAO Xia, LIANG Gui-Zhao. Molecular Design of PTH Derivatives as Tau Protein Inhibitors Using R-Group Search Technology [J]. Chem. J. Chinese Universities, 2012, 33(10): 2263.
[5]	ZHOU Yi-Hui, DUAN Hong-Xia, FU Bin, MA Yong-Qiang, DU Feng-Pei, WANG Ming-An, QIN Zhao-Hai. 3D\\|QSAR Study of Rocaglamide Analogues [J]. Chem. J. Chinese Universities, 2011, 32(5): 1088.
[6]	SHEN Xiao-Xia, XU Sheng-Zhen, CHEN Chang-Shui. 3D-QSAR Study of N-Nitro Urea Derivatives with Herbicidal Activity [J]. Chem. J. Chinese Universities, 2010, 31(12): 2419.
[7]	WANG Mei-Yi, MA Yi, LI Zheng-Ming*, WANG Su-Hua. 3D-QSAR Study of Novel 5-Substituted Benzenesulfonylurea Compounds [J]. Chem. J. Chinese Universities, 2009, 30(7): 1361.
[8]	LI Jia-Bin, LIU Hai-Chun, ZHANG Li, WANG Tao, JIANG Zhen-Zhou3, XIA Lin*. Searching for Novel Lead Compounds of α₁-AR Antagonists: Synthesis, Bioassays and 3D-QSAR of 2-[4-(Aryloxyalkyl)-piperazin-1-yl]benzo[d]oxazole Compounds [J]. Chem. J. Chinese Universities, 2009, 30(5): 903.
[9]	ZHANG Liang, XIANG Yu-Hong, Zhang Zhuo-Yong*. Studies on Hydroxamic Acid Histone Deacetylase Inhibitors(HDACI) by Molecular Docking and CoMFA [J]. Chem. J. Chinese Universities, 2009, 30(11(1)): 52.
[10]	BAN Shu-Rong, NIU Cong-Wei, CHEN Wen-Bin, REN Xiao-Bai, YU Zhi-Hong, XI Zhen. Interaction and CoMFA Studies on A. thaliana Acetohydroxyacid Synthase by Sulfonylureas [J]. Chem. J. Chinese Universities, 2007, 28(3): 543.
[11]	ZHU Jie, SHENG Chun-Quan, ZHANG Min, SONG Yun-Long, CHEN Jun, YU Jian-Xin, YAO Jian-Zhong, LIAO Zhen-Yuan, ZHANG WAN-Nian. 3D-QSAR Study of a Series of Novel Benzofuran NMT Inhibitors [J]. Chem. J. Chinese Universities, 2006, 27(2): 287.
[12]	REN Tian-Rui, SHEN Bin, PEI Jian-Feng, WANG Yong-Sheng, XIANG Wen-Sheng . Pharmacophore Models and 3D-QSAR Studies of Rat and Fly's GABA Receptor Inhibitors [J]. Chem. J. Chinese Universities, 2005, 26(3): 546.
[13]	LIU Ai-Ping, LU Ai-Jun, HUANG Ming-Zhi, CHEN Can, LIU Xing-Ping, LIU Zhao-Jie, YAO Jian-Ren, . 3D-Quantitative Structure-activity Relationship of Insecticidal Oxime-ether Compounds Containing Sulfur(Oxygen) [J]. Chem. J. Chinese Universities, 2005, 26(3): 464.
[14]	HE Yan-Ping, HU Hai-Rong, XU Liao-Sa, MENG Ge, FAN Kan-Nian, CHEN Fen-Er. Structure-activity Relationship Studies on 6-Naphthylmethyl Substituted HEPT Derivatives as Non-nucleoside Reverse Transcriptase Inhibitors Based on Molecular Docking [J]. Chem. J. Chinese Universities, 2005, 26(2): 254.
[15]	MA Yi, JIANG Lin, LI Zheng-Ming, LAI Cheng-Ming . 3D-QSAR Study on N-(4-Substituted pyrimidin-2-yl) Benzyl Sulfonylurea and Phenoxy Sulfonylurea [J]. Chem. J. Chinese Universities, 2004, 25(11): 2031.

Three Dimensional Quantitative Structure-activity Relationship of HEPT Analogues as HIV-1 Reverse Transcriptase Inhibitors

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

References

Related Articles 15

Recommended Articles

Metrics

Comments