Studies of Interaction Mechanism between Pyrido [3,4-d] Pyrimidine Inhibitors and Mps1

Area of Science:

• Biochemistry and Molecular Biology
• Medicinal Chemistry
• Cancer Research

Background:

• Monopolar spindle 1 (Mps1) is a kinase crucial for chromosome segregation and mitotic checkpoint signaling.
• Mps1 overexpression is linked to cancer development and survival of aneuploid cancer cells, making it a viable therapeutic target.
• Novel pyrido[3,4-d]pyrimidine derivatives have shown high biological activity against Mps1.

Purpose of the Study:

• To investigate the binding modes and mechanisms of pyrido[3,4-d]pyrimidine derivatives with Mps1.
• To understand the molecular interactions responsible for the inhibitory activity of these compounds.
• To rationally design new Mps1 inhibitors with improved efficacy.

Main Methods:

• Molecular docking simulations to predict binding poses.
• Molecular dynamics simulations to validate binding stability.
• Molecular mechanics/generalized Born surface area (MM/GBSA) for binding free energy calculations.
• ADMET prediction for newly designed compounds.

Main Results:

• Van der Waals interactions and nonpolar solvation energies contribute significantly to binding free energy.
• All inhibitors consistently interacted with specific Mps1 residues (I531, V539, M602, C604, N606, I607, L654, I663, P673).
• Stable hydrogen bonds formed with Mps1 residues G605 and K529 enhanced inhibitor activity.
• Compounds IV and V emerged as potent Mps1 inhibitors following rational design and ADMET prediction.

Conclusions:

• The study elucidates the detailed binding mechanism of pyrido[3,4-d]pyrimidine derivatives with Mps1.
• Key interactions driving inhibitor efficacy were identified, including van der Waals forces and hydrogen bonds with specific residues.
• The findings provide a foundation for the rational design of novel and more effective Mps1-targeting cancer therapeutics.