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Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays
Published on: September 19, 2018
Targeting MERTK tyrosine kinase: Virtual screening and molecular dynamics insights for anti-cancer drug development
Kashif Kifayat1, Kamaljot Singh2, Mahmood Khan3
1Division of Hepatobiliary and Pancreatic Surgery, Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China.
Abstract:
Global public health facing serious challenges due to the incidence of cancer and the growth of treatment resistance. Mer-tyrosine kinase plays a crucial role in cell biology and correlated with many cancers such as Epithelial ovarian cancer, liver cancer, breast cancer, Metastatic melanoma, and Acute myeloid leukemia (AML). Hence the identification of novel drug for MERTK protein is extreme important. In this research, we used computational techniques, molecular operating environment (MOE 2015) for virtual screening with drug like natural compounds library. We used known compound UNC2025 as positive control and one million compounds was retrieved from different databases (OTAVA, ZINC, ChEMBL) and docked with MERTK protein. Out of million compounds the 4 top hit inhibitors chosen from docking were further screened for ADMET profiling confirming their compliance with drug designing and toxicological principle and subjected to molecular dynamic (MD) simulation and MM-PBSA analysis. The results of these analyses showed that only four compounds that make strong interactions with MERTK protein via highest binding affinity hydrogen bond and hydrophobic contacts (lig1, lig2, lig3, lig4). The computed binding affinity ranges from -22.977 to -18.707 kcal/mol. The increased helix and reduced β-sheet contents in MERTK on the binding of top hit candidates depicted the higher structural stability of MERTK, rather than MERTK alone and MERTK-UNC2025. The study finds critical residues which serve a vital part in binding with the inhibitor and the active site of the MERTK protein, i.e., Phe598, Gly599, Lys619, Arg629, Glu633, Glu637, Arg722, Asp723, Arg727, Asp741, Gly743, Leu744, Lys746, Arg758, Ala760, and Lys761 through decomposed binding free energy analysis. This study focuses on the pursuit of several MERTK protein targets, which could have consequences for the development of novel therapeutics for various cancers.
Insights
This study identifies four novel drug compounds that strongly inhibit MERTK protein, a key target in various cancers. These compounds show promise for developing new cancer therapeutics by stabilizing MERTK protein structure.
Area of Science:
- Computational drug discovery
- Molecular biology
- Cancer research
Background:
- Cancer poses significant global health challenges, exacerbated by treatment resistance.
- MERTK (Mer-tyrosine kinase) is implicated in numerous cancers, including ovarian, liver, breast, melanoma, and AML.
- Targeting MERTK is crucial for developing novel anti-cancer therapeutics.
Purpose of the Study:
- To identify novel MERTK inhibitors using computational screening.
- To evaluate the drug-likeness and binding stability of potential inhibitors.
- To elucidate the molecular interactions between inhibitors and the MERTK active site.
Main Methods:
- Virtual screening of one million natural compounds against MERTK protein using MOE.
- Docking simulations with known inhibitor UNC2025 as a positive control.
- ADMET profiling, molecular dynamics (MD) simulations, and MM-PBSA analysis for top hits.
Main Results:
- Four top hit compounds (lig1-lig4) demonstrated strong binding affinity to MERTK, ranging from -18.707 to -22.977 kcal/mol.
- These compounds formed stable hydrogen bonds and hydrophobic interactions within the MERTK active site.
- Binding of inhibitors increased MERTK's helical content, enhancing structural stability compared to MERTK alone or MERTK-UNC2025.
Conclusions:
- Identified four promising MERTK inhibitors with favorable drug-like properties and high binding affinity.
- Elucidated critical residues (Phe598, Gly599, Lys619, etc.) involved in MERTK-inhibitor interactions.
- These findings provide a foundation for developing novel MERTK-targeted cancer therapies.
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