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Updated: Jun 6, 2026
A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
Discovery of potential RSK1 inhibitors for cancer therapy using virtual screening, molecular docking, molecular
Sevil Kalin1, Ferah Comert Onder2
1Department of Medical System Biology, School of Graduate Students, Çanakkale Onsekiz Mart University, Çanakkale, Türkiye.
Abstract:
The p90 ribosomal protein S6 Kinase (RSK) family belongs to Ser/Thr protein kinases that includes four isoform RSK1-4 in mammals. The ribosomal protein S6 Kinase 1 (RSK1) is also known as ribosomal protein S6 kinase alpha-1 (RPS6KA1) is a special protein due to their two catalytic regions that is associated with abundantly various cancers and it is proposed as a drug target. Several RSK1 isoform inhibitors have been reported but none of them are used in clinical studies. Thus, we aimed to perform ligand pharmacophore mapping with the known inhibitor and structure-based virtual screening studies to determine potential candidates against RSK1-terminal kinase domains CTKD and NTKD. The studied compounds from the databases (ApexBio, ChEMBL, ChemDiv). The molecular docking study was performed with the resulted candidates by using CDOCKER and Glide/SP methods. The four candidates with the highest docking scores were used for further 100-ns molecular dynamics (MD) simulations and Molecular Mechanics Generalised Born and Surface Area (MM/GBSA) calculations. The root mean square deviation (RMSD) for protein complexes were found between 2 Å and 4 Å. Solvent accessible surface area (SASA), radius of gyration (Rg), and polar surface area (PSA) values were calculated for compounds. The binding free energies were calculated between -72.22 kcal/mol and -82.44 kcal/mol. The interaction diagrams showed that hydrogen bond, alkyl, and π-alkyl interactions were observed with specific residues such as Leu144, Lys94, Asp142 for RSK1-NTKD, and Cys532, Cys556, Lys447, Asn540 for RSK1-CTKD. The identified compounds may be potential inhibitor candidates of RSK1 following the preclinical studies.Communicated by Ramaswamy H. Sarma.
Insights
Researchers identified potential drug candidates targeting ribosomal protein S6 Kinase 1 (RSK1) by using computational methods. These novel compounds show promise for cancer therapy, pending further preclinical studies.
Area of Science:
- Biochemistry and Molecular Biology
- Computational Chemistry and Drug Discovery
Background:
- The p90 ribosomal protein S6 Kinase (RSK) family, particularly RSK1 (RPS6KA1), is implicated in various cancers due to its unique dual catalytic regions.
- Despite being a proposed drug target, no RSK1 inhibitors have reached clinical trials, highlighting the need for novel therapeutic strategies.
- RSK1's association with cancer necessitates the development of effective inhibitors for potential therapeutic interventions.
Purpose of the Study:
- To identify potential drug candidates targeting the terminal kinase domains (CTKD and NTKD) of ribosomal protein S6 Kinase 1 (RSK1).
- To perform ligand pharmacophore mapping and structure-based virtual screening to discover novel RSK1 inhibitors.
- To evaluate the binding affinity and stability of identified compounds using molecular dynamics and MM/GBSA calculations.
Main Methods:
- Utilized ligand pharmacophore mapping and virtual screening of compounds from ApexBio, ChEMBL, and ChemDiv databases.
- Employed molecular docking (CDOCKER and Glide/SP) to assess binding interactions with RSK1-CTKD and RSK1-NTKD.
- Conducted 100-ns molecular dynamics (MD) simulations and MM/GBSA calculations for top-scoring candidates, analyzing RMSD, SASA, Rg, and PSA.
Main Results:
- Identified four promising candidate compounds with high docking scores and favorable binding free energies ranging from -72.22 to -82.44 kcal/mol.
- Molecular dynamics simulations showed protein complex stability with RMSD values between 2 Å and 4 Å.
- Detailed interaction analysis revealed key interactions, including hydrogen bonds and π-alkyl interactions, with specific RSK1 residues (e.g., Leu144, Lys94, Asp142 for NTKD; Cys532, Cys556, Lys447, Asn540 for CTKD).
Conclusions:
- The identified compounds demonstrate significant potential as RSK1 inhibitors based on computational analyses.
- These candidates warrant further investigation in preclinical studies as novel therapeutic agents against RSK1-associated cancers.
- The study provides a foundation for the rational design of more potent and selective RSK1 inhibitors.
