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Published on: June 4, 2021
In Silico Analysis of USP7 Inhibitors Based on Building QSAR Models and Fragment Design for Screening Marine Compound
Huiting Tan1, Chenying Li1, Tianli Lai1
1The First Clinical College, Guangdong Medical University, Zhanjiang 524023, China.
Abstract:
USP7 is highly expressed in a variety of tumors and is thought to play a major role in cancer development. However, there are no drugs available to target USP7, so there is a need to develop new USP7 inhibitors. In this study, AutoQSAR, multiple linear regression, and Naive Bayesian models were constructed using 543 compounds and used to analyze marine compounds. After selecting 240 small molecules for molecular docking with Maestro, MOE, and GOLD, better small molecules than the positive compound P217564 were screened. The molecular structure of "1, 2-dibromobenzene" was optimized to improve the binding effect of the protein, and 10 optimized compounds in ADMET performed well during the screening process. To study the dynamic combination of protein-ligand effect consistency with static molecular docking, 100ns molecular dynamics simulations of candidate compound 1008-1, reference compound P217564, and negative-positive GNE2917 were conducted. The results of molecular docking and molecular dynamics simulation analysis showed that compound 1008-1 maintained a stable conformation with the target protein. Thus, the comprehensive analysis suggests that compound 1008-1 could provide new possibilities for USP7 covalent inhibitor candidates.
Insights
Researchers identified a novel USP7 inhibitor candidate, compound 1008-1, by analyzing marine compounds using computational methods. This discovery offers potential new avenues for developing targeted cancer therapies against USP7, a key protein in tumor development.
Area of Science:
- Computational Chemistry
- Drug Discovery
- Oncology
Background:
- Ubiquitin-specific protease 7 (USP7) is highly expressed in various tumors, indicating its significant role in cancer development.
- Currently, no drugs are available to target USP7, highlighting an unmet need for novel USP7 inhibitors.
Purpose of the Study:
- To identify and develop novel small molecules as potential inhibitors targeting USP7.
- To explore marine compounds as a source for new USP7 inhibitor candidates.
Main Methods:
- Utilized AutoQSAR, multiple linear regression, and Naive Bayesian models with 543 compounds for quantitative structure-activity relationship analysis.
- Performed molecular docking using Maestro, MOE, and GOLD on 240 selected small molecules.
- Conducted 100ns molecular dynamics simulations to assess the stability and binding of candidate compounds.
Main Results:
- Screened small molecules superior to the positive control P217564.
- Optimized the molecular structure of 1,2-dibromobenzene, leading to 10 compounds with favorable ADMET properties.
- Compound 1008-1 demonstrated stable conformation and binding with USP7, confirmed by molecular docking and dynamics simulations.
Conclusions:
- Compound 1008-1 emerged as a promising candidate for developing USP7 covalent inhibitors.
- The study provides a foundation for further development of targeted therapies against USP7 in cancer treatment.
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