Affiliation:
1. National Institute of Pharmaceutical Education and Research (NIPER) S.A.S. Nagar
Abstract
Abstract
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.
Publisher
Research Square Platform LLC
Reference50 articles.
1. In silico approach for bioremediation of arsenic by structure prediction and docking studies of arsenite oxidase from Pseudomonas stutzeri TS44;Akhter M;Int Biodeterior Biodegradation Elsevier,2017
2. Albert M, Helin K (2010) Histone methyltransferases in cancer. Semin. Cell Dev. Biol. Elsevier; p. 209–20
3. Allali-Hassani A, Kuznetsova E, Hajian T, Wu H, Dombrovski L, Li Y et al (2014) A basic post-SET extension of NSDs is essential for nucleosome binding in vitro. J. Biomol. Screen. SAGE Publications Sage CA: Los Angeles, CA; ;19(6):928–35
4. NSD3, a new SET domain-containing gene, maps to 8p12 and is amplified in human breast cancer cell lines;Angrand P-O;Genomics Elsevier,2001
5. NSD2 is a conserved driver of metastatic prostate cancer progression;Aytes A;Nat Commun Nature Publishing Group,2018