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Published on: June 13, 2019
Target validation and structure-based virtual screening to Discover potential lead molecules against the oncogenic
Zahid Rafiq Bhat1, Anuj Gahlawat2, Navneet Kumar2
1Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, India.
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.
Supplementary Information:
The online version contains supplementary material available at 10.1007/s40203-023-00158-0.
Insights
This study validates Nuclear receptor-binding SET Domain NSD1 as a cancer drug target. Promising lead compounds were designed using structure-based virtual screening for future cancer therapeutics development.
Area of Science:
- Oncology
- Drug Discovery
- Computational Chemistry
Background:
- Nuclear receptor-binding SET Domain NSD1 plays a role in various malignancies, influencing metastasis, prognosis, and overall survival.
- Understanding NSD1's role is crucial for developing novel cancer therapeutics.
Purpose of the Study:
- To validate NSD1 as a viable cancer drug target.
- To design novel small molecules as potential inhibitors of NSD1.
Main Methods:
- Utilized TCGA clinical data and molecular expression techniques for target validation.
- Employed structure-based virtual screening against NSD1 using ZINC15 and ChemDiv databases.
- Performed molecular dynamic simulations and MMGBSA calculations on top-ranked compounds.
Main Results:
- Clinical data analysis confirmed NSD1's association with cancer progression and survival.
- Virtual screening identified potential NSD1 inhibitors, with ZINC000257261703 and ZINC000012405780 showing favorable binding energies.
- These compounds demonstrated lower MMGBSA energy compared to sinefungin, indicating potent binding to NSD1's cofactor site.
Conclusions:
- NSD1 is validated as a promising cancer drug target.
- Identified lead compounds provide a strong foundation for further optimization in rational drug design for cancer treatment.
