本研究的目的是验证核受体结合SET区域NSD1作为一种癌症药物靶标，然后设计针对NSD1的先导分子。研究使用TCGA临床数据、分子表达技术验证了该靶点，并通过基于结构的虚拟筛选设计了针对NSD1的候选化合物。临床数据分析显示NSD1在多种恶性肿瘤中的转移、预后和总生存的作用。此外，还在多种细胞系中评估了NSD1的mRNA和蛋白质表达谱。通过基于结构的虚拟筛选方法，在两个主要数据库（包括ZINC15和ChemDiv）中利用蛋白复合物S-腺苷甲硫氨酸（SAM）作为内源配体，开发了针对NSD1的抑制剂。随后，通过组合得分来区分具有在所有四个得分（对接得分、XP得分、Gscore得分、PhaseScreenScore得分和MMGBSA delta G Bind得分）中表现良好的前10个化合物。最后，将前三个Zinc化合物进行分子动力学模拟。结合MMGBSA数据的结合位点提示，ZINC000257261703和ZINC000012405780较辛呋胺对NSD1的辅因子结合位点具有更低的MMGBSA能量。我们的数据验证了NSD1作为癌症药物靶标，并提供了有前景的结构，可用于进一步的先导优化和合理药物设计，为癌症治疗领域开辟新的道路。在线版本包含补充材料，网址为10.1007/s40203-023-00158-0。© 作者，与Springer-Verlag GmbH Germany的独家许可，Springer Nature 2023的一部分。Springer Nature或其许可方（如学会或其他合作方）根据与作者或其他权利持有人达成的出版协议，对本文章拥有独家权利；对所接受的手稿版本进行作者自行归档，仅受此类出版协议和适用法律的限制。

The aim of the study was to validate Nuclear receptor-binding SET Domain NSD1 as a cancer drug target followed by the design of lead molecules against NSD1. TCGA clinical data, molecular expression techniques were used to validate the target and structure-based virtual screening was performed to design hits against NSD1. Clinical data analysis suggests the role of NSD1 in metastasis, prognosis and influence on overall survival in various malignancies. Furthermore, the mRNA and protein expression profile of NSD1 was evaluated in various cell lines. NSD1 was exploited as a target protein for in silico design of inhibitors using two major databases including ZINC15 and ChemDiv by structure-based virtual screening approach. Virtual screening was performed using the pharmacophore hypothesis designed with a protein complex S-adenosyl-l-methionine (SAM) as an endogenous ligand. Subsequently, a combined score was used to distinguish the top 10 compounds from the docking screened compounds having high performance in all four scores (docking score, XP, Gscore, PhaseScreenScore, and MMGBSA delta G Bind). Finally, the top three Zinc compounds were subjected to molecular dynamic simulation. The binding MMGBSA data suggests that ZINC000257261703 and ZINC000012405780 can be taken for in vitro and in vivo studies as they have lesser MMGBSA energy towards the cofactor binding site of NSD1 than the sinefungin. Our data validates NSD1 as a cancer drug target and provides promising structures that can be utilized for further lead optimization and rational drug design to open new gateways in the field of cancer therapeutics.The online version contains supplementary material available at 10.1007/s40203-023-00158-0.© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.