Related Experiment Videos
Docking-based structural splicing and reassembly strategy to develop novel deazapurine derivatives as potent
Gui-Min Wang1,2, Xiang Wang3, Jian-Ming Zhu1
1CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Abstract:
The mutation of B-RafV600E is widespread in a variety of human cancers. Its inhibitors vemurafenib and dabrafenib have been launched as drugs for treating unresectable melanoma, demonstrating that B-RafV600E is an ideal drug target. This study focused on developing novel B-RafV600E inhibitors as drug leads against various cancers with B-RafV600E mutation. Using molecular modeling approaches, 200 blockbuster drugs were spliced to generate 283 fragments followed by molecular docking to identify potent fragments. Molecular structures of potential inhibitors of B-RafV600E were then obtained by fragment reassembly followed by docking to predict the bioactivity of the reassembled molecules. The structures with high predicted bioactivity were synthesized, followed by in vitro study to identify potent B-RafV600E inhibitors. A highly potent fragment binding to the hinge area of B-RafV600E was identified via a docking-based structural splicing approach. Using the fragment, 14 novel structures were designed by structural reassembly, two of which were predicted to be as strong as marketed B-RafV600E inhibitors. Biological evaluation revealed that compound 1m is a potent B-RafV600E inhibitor with an IC50 value of 0.05 μmol/L, which was lower than that of vemurafenib (0.13 μmol/L). Moreover, the selectivity of 1m against B-RafWT was enhanced compared with vemurafenib. In addition, 1m exhibits desirable solubility, bioavailability and metabolic stability in in vitro assays. Thus, a highly potent and selective B-RafV600E inhibitor was designed via a docking-based structural splicing and reassembly strategy and was validated by medicinal synthesis and biological evaluation.
Insights
Researchers developed novel B-RafV600E inhibitors using molecular modeling and fragment-based drug design. Compound 1m emerged as a potent and selective inhibitor, outperforming vemurafenib in vitro, with favorable drug-like properties.
Area of Science:
- Medicinal Chemistry
- Molecular Pharmacology
- Drug Discovery
Background:
- The B-RafV600E mutation is prevalent in various human cancers, making it a critical therapeutic target.
- Approved inhibitors like vemurafenib highlight the potential of targeting B-RafV600E, necessitating the development of novel agents.
Purpose of the Study:
- To design and synthesize novel inhibitors targeting the B-RafV600E mutation for cancer therapy.
- To identify potent and selective drug leads with improved pharmacological profiles.
Main Methods:
- Utilized molecular modeling, including fragment splicing and molecular docking, to identify potential B-RafV600E inhibitor fragments from blockbuster drugs.
- Employed fragment reassembly and docking to design novel inhibitor structures, followed by synthesis and in vitro biological evaluation.
Main Results:
- Identified a potent fragment targeting the B-RafV600E hinge region.
- Designed and synthesized 14 novel compounds, with compound 1m demonstrating superior potency (IC50 = 0.05 μmol/L) compared to vemurafenib (0.13 μmol/L).
- Compound 1m exhibited enhanced selectivity against wild-type B-Raf (B-RafWT) and favorable in vitro properties including solubility, bioavailability, and metabolic stability.
Conclusions:
- A novel B-RafV600E inhibitor, compound 1m, was successfully designed using a docking-based fragment splicing and reassembly strategy.
- Compound 1m represents a promising drug lead for treating cancers with B-RafV600E mutations, offering improved potency and selectivity over existing therapies.