Hydroxyalkynyl uracil derivatives as NNRTIs against HIV-1: in silico predictions, synthesis, docking and molecular dynamics simulation studies

尿嘧啶 化学 对接(动物) 立体化学 核苷 核苷逆转录酶抑制剂 胸腺嘧啶 逆转录酶 嘧啶 分子模型 生物信息学 组合化学 生物化学 核糖核酸 DNA 医学 护理部 基因
作者
Madhu Yadav,Ritika Srivastava,Farha Naaz,Parth Sarthi Sen Gupta,Saroj Kumar Panda,Malay Kumar Rana,R. K. P. Singh
出处
期刊:Journal of Biomolecular Structure & Dynamics [Taylor & Francis]
卷期号:41 (16): 8068-8080
标识
DOI:10.1080/07391102.2022.2130980
摘要

To improve rationally the efficacy of the non-nucleoside human immunodeficiency virus (HIV-1) inhibitors, it is important to have a precise and detailed understanding of the HIV-1 reverse transcriptase (RT) and inhibitor interactions. For the 1-[(2-hydroxyethoxy) methyl]-6-(phenylthio) thymine (HEPT) type of nucleoside reverse transcriptase inhibitors (NNRTIs), the H-bond between the N-3H of the inhibitor and the backbone carbonyl group of K101 represents the major hydrophilic interaction. This H-bond contributes to the NNRTI binding affinity. The descriptor analyses of different uracil derivatives proved their good cell internalization. The bioactivity score reflected higher drug likeness score and the ligands showed interesting docking results. All molecules were deeply buried and stabilized into the allosteric site of HIV-1 RT. For majority of molecules, residues Lys101, Lys103, Tyr181 and Tyr188 were identified as key protein residues responsible for generation of H-bond and major interactions were similar to all known NNRTIs while very few molecules interacted with residues Phe227 and Tyr318. The TOPKAT protocol available in Discovery Studio 3.0 was used to predict the pharmacokinetics of the designed uracil derivatives in the human body. The molecular dynamics (MD) and post-MD analyses results reflected that the complex HIVRT:5 appeared to be more stable than the complex HIVRT:HEPT, where HEPT was used as reference. Different uracil derivatives have been synthesized by using uracil as starting material and commercially available propargyl bromide. The N-1 derivative of uracil was further reacted with sodamide and different aldehydes/ketones bearing alkyl and phenyl ring to obtain hydroxyalkynyl uracil derivatives as NNRTIs.Communicated by Ramaswamy H. Sarma.
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