Dalhat Mahmood Hassan, Altayb Hisham N, Khan Mohammad Imran, Choudhry Hani
Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
Centre for Artificial Intelligence in Precision Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
Sci Rep. 2021 Mar 15;11(1):6051. doi: 10.1038/s41598-021-84908-0.
N-acetyltransferase 10 (NAT10), is an acetyltransferase that regulates RNA stability and translation processes. Association of NAT10 with several diseases including cancer, makes it a promising therapeutic target. Remodelin is the only known NAT10 inhibitor, but the structural information related to its binding with NAT10 is still obscure. Here, we predicted the human NAT10 structure using homology modeling that was not available previously and used human NAT10 to identify the novel binding site(s) of Remodelin. The alignment of the modeled human NAT10 showed 24% identity and 37% positivity with crystal structure of tRNA (Met) cytidine acetyltransferase. Molecular docking showed binding of Remodelin with NAT10 in acetyl-CoA binding pocket. Additionally, we screened a library of FDA-approved drugs for the identification of novel inhibitors of NAT10 activity. Binding score showed that four drugs namely, Fosaprepitant (- 11.709), Leucal (- 10.46), Fludarabine (- 10.347) and Dantrolene (- 9.875) bind to NAT10 and have better binding capability when compared with Acetyl-CoA (- 5.691) and Remodelin (- 5.3). Acetyl-CoA, Remodelin, and others exhibit hits for hydrophobic, hydrophilic and hydrogen interactions. Interestingly, Remodelin and others interact with the amino acid residues ILE629, GLY639, GLY641, LEU719, and PHE722 in the Acetyl-CoA binding pocket of NAT10 similar to Acetyl-CoA. Our findings revealed that Fosaprepitant, Leucal, Fludarabine, and Dantrolene are promising molecules that can be tested and developed as potential inhibitors of NAT10 acetyltransferase activity.
N-乙酰转移酶10（NAT10）是一种调节RNA稳定性和翻译过程的乙酰转移酶。NAT10与包括癌症在内的多种疾病相关，使其成为一个有前景的治疗靶点。Remodelin是唯一已知的NAT10抑制剂，但其与NAT10结合的结构信息仍不清楚。在这里，我们使用以前没有的同源建模预测了人类NAT10的结构，并利用人类NAT10来确定Remodelin的新结合位点。建模的人类NAT10与tRNA（Met）胞苷乙酰转移酶的晶体结构显示出24%的同一性和37%的阳性率。分子对接显示Remodelin与NAT10在乙酰辅酶A结合口袋中结合。此外，我们筛选了一个FDA批准的药物库，以鉴定NAT10活性的新型抑制剂。结合分数显示，四种药物即福沙匹坦（-11.709）、亮卡（-10.46）、氟达拉滨（-10.347）和丹曲林（-9.875）与NAT10结合，与乙酰辅酶A（-5.691）和Remodelin（-5.3）相比具有更好的结合能力。乙酰辅酶A、Remodelin和其他物质表现出疏水、亲水和氢键相互作用的命中情况。有趣的是，Remodelin和其他物质与NAT10的乙酰辅酶A结合口袋中的氨基酸残基ILE629、GLY639、GLY641、LEU719和PHE722相互作用，类似于乙酰辅酶A。我们的研究结果表明，福沙匹坦、亮卡、氟达拉滨和丹曲林是有前景的分子，可以作为NAT10乙酰转移酶活性的潜在抑制剂进行测试和开发。
