BioChem - DOS

Highly Accessible Computational Prediction and In Vivo/In Vitro Experimental Validation: Novel Synthetic Phenyl Ketone Derivatives as Promising Agents against NAFLD via Modulating Oxidoreductase Activity

Oxidative medicine and cellular longevity

Qiao, Yanan; Deng, Huifang; Liu, Lihua; Liu, Shuran; Ren, Luyao; Shi, Chuandao; Chen, Xi; Guan, Lixia; Liu, Weiran; Li, Zehua; Li, Yunlan

<P>Nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions with no pharmacological treatment approved. Several highly accessible computational tools were employed to predict the activities of twelve novel compounds prior to actual chemical synthesis. We began our work by designing two or three hydroxyl groups appended to the phenyl ketone core, followed by prediction of drug-likeness and targets. Most predicted targets for each compound overlapped with NAFLD targets (&ge;80%). Enrichment analysis showed that these compounds might regulate oxidoreductase activity. Then, these compounds were synthesized and confirmed by IR, MS, <SUP>1</SUP>H, and <SUP>13</SUP>C NMR. Their cell viability demonstrated that twelve compounds exhibited appreciable potencies against NAFLD (EC<SUB>50</SUB> values &le; 13.5 <I>&mu;</I>M). Furthermore, the most potent compound <B>5f</B> effectively prevented NAFLD progression as evidenced by the change in histological features. <B>5f</B> significantly reduced total cholesterol and triglyceride levels <I>in vitro/in vivo</I>, and the effects of <B>5f</B> were significantly stronger than those of the control drug. The proteomic data showed that oxidoreductase activity was the most significantly enriched, and this finding was consistent with docking results. In summary, this validated presynthesis prediction approach was cost-saving and worthy of popularization. The novel synthetic phenyl ketone derivative <B>5f</B> holds great therapeutic potential by modulating oxidoreductase activity to counter NAFLD.</P>

2023

Hindawi

1942-0900

1942-0994

2023

pp.3782230

10.1155/2023/3782230

http://click.ndsl.kr/servlet/OpenAPIDetailView?keyValue=05787966&target=NART&cn=NART122945648