Effective virtual screening strategy toward JAK3 covalent inhibitors: combining multi‑conformational consensus...

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Computational Biology

Background:

• Overactivation of Janus kinase 3 (JAK3) is linked to inflammatory and autoimmune diseases.
• Existing JAK3 inhibitors lack selectivity due to high kinase homology.
• Covalent inhibitors offer a promising strategy for improved JAK3 selectivity.

Purpose of the Study:

• To develop and validate a hierarchical virtual screening cascade for identifying novel covalent JAK3 inhibitors.
• To enhance selectivity of JAK3 inhibitors through a covalent docking approach.
• To screen a chemical database for potential covalent JAK3 inhibitors.

Main Methods:

• A hierarchical virtual screening cascade combining non-covalent and covalent docking.
• Consensus scoring virtual screening with pharmacophore modeling and non-covalent molecular docking.
• Covalent molecular docking targeting CYS909 residue in JAK3.
• Validation of the screening method for accuracy and efficiency.

Main Results:

• The developed virtual screening cascade demonstrated high accuracy and efficiency.
• Screening of the SPECS database identified several potential covalent JAK3 inhibitors.
• The identified compounds show promise for targeting JAK3 in inflammatory conditions.

Conclusions:

• The hierarchical virtual screening cascade is an effective strategy for discovering selective covalent JAK3 inhibitors.
• This method advances the development of targeted therapies for inflammatory and autoimmune disorders.
• Novel covalent JAK3 inhibitors were identified, warranting further investigation.