Discovery of potential RSK1 inhibitors for cancer therapy using virtual screening, molecular docking, molecular dynamics simulation, and MM/GBSA calculations
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Tarih
2025
Yazarlar
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Taylor & Francis Inc
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
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 & Aring; and 4 & Aring;. 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 pi-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.
Açıklama
Anahtar Kelimeler
RSK1, virtual screening, ADMET, pharmacophore, molecular docking, MD simulation, MM/GBSA
Kaynak
Journal of Biomolecular Structure & Dynamics
WoS Q Değeri
Q2
Scopus Q Değeri
Q1
Cilt
43
Sayı
3
