Discovery of potential ALK inhibitors by virtual screening approach
Anish Kumar1, V Shanthi1, K Ramanathan2
1Industrial Biotechnology Division, School of Bio Sciences and Technology, VIT University, Vellore, Tamil Nadu, 632014, India.
Abstract:
Crizotinib is an anticancer drug used for the treatment of non-small cell lung cancer. Evidences available suggest that there is a development of an acquired resistance against crizotinib action due to the emergence of several mutations in the ALK gene. It is therefore necessary to develop potent anti-cancer drugs for the treatment of crizotinib resistance non-small cell lung cancer types. In the present study, a novel class of lead molecule was identified using virtual screening, molecular docking and molecular dynamic approach. The virtual screening analysis was done using PubChem database by employing crizotinib as query and the data reduction was carried out by using molecular docking techniques. The bioavailability of the lead compounds was examined with the help of Lipinski rule of five. The screened lead molecules were analyzed for toxicity profiles, drug-likeness and other physico-chemical properties of drugs by OSIRIS program. Finally, molecular dynamics simulation was also performed to validate the binding property of the lead compound. Our analysis clearly indicates that CID 11562217, a nitrile containing compound (pyrazole-substituted aminoheteroaryl), could be the potential ALK inhibitor certainly helpful to overcome the drug resistance in non-small cell lung cancer.
Insights
Researchers identified a new potential drug, CID 11562217, to combat drug resistance in non-small cell lung cancer (NSCLC). This novel compound may overcome resistance to crizotinib by inhibiting the ALK gene.
Area of Science:
- Medicinal Chemistry
- Computational Drug Discovery
- Oncology
Background:
- Crizotinib is a targeted therapy for non-small cell lung cancer (NSCLC) with an anaplastic lymphoma kinase (ALK) fusion.
- Acquired resistance to crizotinib, often due to ALK gene mutations, limits its long-term efficacy.
- Development of novel inhibitors is crucial to overcome crizotinib resistance in NSCLC.
Purpose of the Study:
- To identify novel small molecules capable of inhibiting ALK.
- To discover potential drug candidates for treating crizotinib-resistant NSCLC.
- To computationally screen and validate new ALK inhibitors.
Main Methods:
- Virtual screening of chemical databases (PubChem) using crizotinib as a reference.
- Molecular docking and molecular dynamics simulations to assess binding affinity and stability.
- In silico analysis of drug-likeness, bioavailability (Lipinski's Rule of Five), and toxicity profiles (OSIRIS).
Main Results:
- A novel class of pyrazole-substituted aminoheteroaryl compounds was identified.
- CID 11562217 demonstrated promising binding affinity and stability against ALK.
- In silico ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) properties suggest favorable drug-likeness for CID 11562217.
Conclusions:
- CID 11562217, a nitrile-containing compound, is a potential ALK inhibitor.
- This molecule shows promise for overcoming acquired resistance to crizotinib in NSCLC.
- Further experimental validation is warranted to confirm its therapeutic potential.
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