Introduction:Human Immunodeficiency Virus (HIV) has become an epidemic causing Acquired Immunodeficiency Syndrome (AIDS). Highly active antiretroviral therapy (HAART) consists of Nucleoside Reverse Transcriptase Inhibitors (NRTIS), Nucleotide Reverse Transcriptase Inhibitors (NtRTIS), and Non- Nucleoside Reverse Transcriptase Inhibitors (NNRTIS) with HIV Protease Inhibitors (HIV PIs). However, the emergence of resistant strains of NNRTIS necessitates the search for better HIV-1-RT inhibitors.Methods:In this study, a series of novel imidazoles (SP01-SP30) was designed using molecular docking inside the non-nucleoside inhibitory binding pocket (NNIBP) of the HIV-1-RT (PDB ID-1RT2) using Glide v13.0.137, Autodock Vina, and FlexX v2.1.3. Prime MMGBSA was used to study the free energy of binding of the inhibitors with the target enzyme. Molecular dynamics simulation studies were carried out to discover the dynamic behavior of the protein as well as to unveil the role of the essential amino acids required for the better binding affinity of the inhibitor within the NNIBP of the enzyme. The QikProp software module of Schrodinger and online SwissADME were also used to evaluate the drug-likeliness of these compounds.Results:The imidazole derivative SP08 is predicted to be the most promising design compound that can be considered for further synthetic exploitations to obtain a molecule with the highest therapeutic index against HIV-1-RT.Conclusion:The results of the current study demonstrate the robustness of our in-silico drug design strategy that can be used for the discovery of novel HIV-1-RT inhibitors.

2020-02-01·European Journal of Medicinal Chemistry

Design, synthesis and evaluation of diosgenin carbamate derivatives as multitarget anti-Alzheimer’s disease agents

Article

作者: Huang, Yan ; Zheng, Lu-Lu ; Huang, Jin ; Yang, Gui-Xiang ; Wu, Yu-Hang ; Zhang, Li ; Zhou, Li-Cheng ; Tang, Yun ; Wang, Rui ; Su, Lin ; Li, Jie ; Ma, Lei

In order to produce an effective and multi-targeted clinical drug that could prevent progressive neurodegeneration, a series of diosgenin carbamate derivatives were designed, synthesized and tested for their anti-inflammatory, antioxidant and anti-Aβ activities. The results demonstrated that compound M15 was the most promising derivative against inflammatory (NO inhibition 22.7 ± 2.2%,10 μM) and cellular damage induced by H₂O₂ (SH-SY5Y cell protection = 75.3 ± 3.4%, 10 μM) or Aβ (astrocytes protection = 70.2 ± 6.5%, 10 μM). Molecular docking studies revealed the strong binding affinity of M15 to the active site of nNOS, Aβ₄₂ and pro-inflammatory proteins. Western blot demonstrated that M15 decreased IL-1β, IL-6 and TNF-α level, which may contribute to its anti-inflammatory effects. In addition, M15 maintained mitochondrial function as well as cell viability through reducing H₂O₂-induced ROS production. The results indicated that oral administration of M15 attenuated memory deficits and played a neuroprotective effect on subcutaneous (s.c.) D-gal aging mice. In summary, M15 could be considered as a potential multifunctional neuroprotective agent due to the effects of anti-inflammatory, antioxidant and anti-Aβ activities.

2018-08-01·European Journal of Medicinal Chemistry1区 · 医学

Design, synthesis and biological evaluation of 3-piperazinecarboxylate sarsasapogenin derivatives as potential multifunctional anti-Alzheimer agents

1区 · 医学

Article

作者: Ge, Song-Lan ; Huang, Jin ; Yang, Gui-Xiang ; Li, Shi-Liang ; Ma, Lei ; Wang, Rui ; Wu, Yan

A series of multifunctional 3-piperazinecarboxylate sarsasapogenin derivatives were designed and synthesized against Alzheimer's disease (AD). The protection against H₂O₂-triggered oxidative stress in PC12 cells, and inhibition on LPS-induced NO production in RAW264.7 cell lines in vitro by these derivatives were firstly evaluated. Most of the compounds showed better antioxidant and antiinflammatory activities compared with sarsasapogenin, especially AA34 and AA36. Structure-activity relationships revealed that benzyl group, electron-donating group and intramolecular hydrogen bond might be beneficial to enhancing their neuroprotective activities. Moreover, Aβ42 was the optimum predicted target based on the high 3D molecular similarity between compound AA36 and caprospinol. In the following experiments, AA36 significantly protected PC12 cells from Aβ-induced damage and improved learning and memory impairments in Aβ-injected mice. Thus AA36 is regarded as a potent anti-AD agent and N-substituted piperazinecarboxylate can be served as a promising structural unit for anti-AD drug design.

100 项与 Caprospinol 相关的药物交易

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