Mechanistic Insights into the Mechanism of Inhibitor Selectivity toward the Dark Kinase STK17B against Its High Homology STK17A

Molecules, Год журнала: 2022, Номер 27(14), С. 4655 - 4655

Опубликована: Июль 21, 2022

As a member of the death-associated protein kinase (DAPK) family, STK17B plays an important role in regulation cellular apoptosis and has been considered as promising drug target for hepatocellular carcinoma. However, highly conserved ATP-binding site kinases represents challenge to design selective inhibitors specific DAPK isoform. In this study, molecular docking, multiple large-scale dynamics (MD) simulations, binding free energy calculations were performed decipher mechanism selectivity PKIS43 toward against its high homology STK17A. MD simulations revealed that STK17A underwent significant conformational arrangement activation loop compared STK17B. The predictions suggested driving force control was derived from difference protein-ligand electrostatic interactions. Furthermore, per-residue decomposition unveiled contribution Arg41 at phosphate-binding determinant factor responsible specificity PKIS43. This study may provide useful information rational novel potent

Язык: Английский

---

Drug discovery processes: When and where the rubber meets the road

Elsevier eBooks, Год журнала: 2023, Номер unknown, С. 339 - 415

Опубликована: Янв. 1, 2023

Язык: Английский

---

Leveraging the Fragment Molecular Orbital Method to Explore the PLK1 Kinase Binding Site and Polo-Box Domain for Potent Small-Molecule Drug Design

Опубликована: Сен. 19, 2023

Polo-like kinase 1 (PLK1) plays a pivotal role in cell division regulation and emerges as promising therapeutic target for cancer treatment. Consequently, the development of small-molecule inhibitors targeting PLK1 has become focal point contemporary research. The adenosine triphosphate (ATP)-binding site polo-box domain present crucial interaction sites these inhibitors, aiming to disrupt protein's function. However, designing potent selective can be challenging, requiring deep understanding protein-ligand mechanisms at binding sites. In this context, our study leverages fragment molecular orbital (FMO) method explore site-specific interactions in-depth. Through FMO approach, we used elucidate drug design that are both selective. Our investigation further entailed comparative analysis various each characterized by distinct structural attributes. This comparison enhanced structure-activity relationships underscoring efficacy identifying critical features predicting modes ligands. Furthermore, research spotlighted "hot spot" residues instrumental robust binding. findings offer profound insights, priming rational innovative potential with significant implications developing anticancer therapeutics.

Язык: Английский

---

Revisiting Structure-activity Relationships: Unleashing the potential of selective Janus kinase 1 inhibitors

Bioorganic Chemistry, Год журнала: 2024, Номер 149, С. 107506 - 107506

Опубликована: Май 29, 2024

Язык: Английский

---

Anticancer and Anti-Inflammatory Effects of Novel Ethyl Pyrazole Derivatives Having Sulfonamide Terminal Moiety

Опубликована: Янв. 1, 2024

Язык: Английский

---