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Discovery of potential AXL inhibitors using virtual screening, molecular docking, molecular dynamics, molecular
Nebahat Sahin1, Alper Onder2, Nermin Kahraman3
1Department of Medical System Biology, School of Graduate Students, Çanakkale Onsekiz Mart University, 17020, Çanakkale, Turkey.
Abstract:
AXL is overexpressed in many cancers, including breast, lung, colon, osteosarcoma, kidney, stomach, and gliomas, and associated with poor patient survival and plays an important role in cancer cell proliferation, survival, tumor growth, progression and metastasis. In vivo studies involving genetic targeting of AXL validated it as a promising therapeutic target. In this study, we performed integrated in silico analyses, including virtual screening, molecular docking, molecular dynamics (MD) simulations, and MM/GBSA calculations to search the compound libraries from various small molecule databases to identify potential inhibitors targeting AXL. We identified key amino acid residues such as Met623, Pro621, Asp627, and Asp690 located in the binding pocket of AXL interacting with the potential inhibitors and positive control compounds through with hydrogen and pi-pi bonds. In vitro studies with the three lead compounds (STOCK1N-80636, STOCK1N-66436 and Nebivolol) demonstrated significant antiproliferative effects in four different breast cancer cell lines STOCK1N-80636 was being the most potent. In conclusion, these findings have enabled the identification of potential AXL inhibitors through integrated in silico and in vitro results.
Insights
Researchers identified potential AXL inhibitors for cancer therapy. Integrated computational and laboratory studies pinpointed compounds like STOCK1N-80636, showing significant antiproliferative effects against breast cancer cells.
Area of Science:
- Oncology
- Computational Chemistry
- Pharmacology
Background:
- AXL receptor tyrosine kinase is overexpressed in numerous cancers, correlating with poor patient outcomes.
- AXL signaling drives cancer cell proliferation, survival, tumor growth, metastasis, and progression.
- Genetic targeting of AXL has shown promise as a therapeutic strategy in preclinical cancer models.
Purpose of the Study:
- To identify novel small molecule inhibitors targeting the AXL receptor.
- To utilize integrated in silico and in vitro approaches for drug discovery.
Main Methods:
- Virtual screening, molecular docking, molecular dynamics (MD) simulations, and MM/GBSA calculations were employed.
- Compound libraries from small molecule databases were screened against AXL.
- In vitro antiproliferative assays were conducted using lead compounds against breast cancer cell lines.
Main Results:
- Key amino acid residues (Met623, Pro621, Asp627, Asp690) in the AXL binding pocket were identified as crucial interaction points.
- Three lead compounds (STOCK1N-80636, STOCK1N-66436, Nebivolol) were identified.
- STOCK1N-80636 exhibited the most potent antiproliferative activity in breast cancer cell lines.
Conclusions:
- Integrated in silico and in vitro analyses successfully identified potential AXL inhibitors.
- The identified compounds, particularly STOCK1N-80636, represent promising candidates for further development in AXL-targeted cancer therapy.
