3D-QSAR studies on antitubercular thymidine monophosphate kinase inhibitors based on different alignment methods

Area of Science:

• Medicinal Chemistry
• Computational Biology
• Drug Discovery

Background:

• Tuberculosis remains a significant global health threat, necessitating novel therapeutic strategies.
• Thymidine monophosphate kinase (TMPK) is a validated drug target in Mycobacterium tuberculosis.
• Deoxythymidine monophosphate (dTMP) derivatives are explored for their inhibitory potential against TMPK.

Purpose of the Study:

• To develop and validate 3D-QSAR models for dTMP derivatives inhibiting TMPK.
• To identify key structural features contributing to the antitubercular activity.
• To provide a basis for the rational design of novel TMPK inhibitors.

Main Methods:

• Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed.
• Molecular Field Analysis (MFA) was employed using three alignment techniques: least squares, pharmacophore-based, and receptor-based.
• Model performance was evaluated and compared across different alignment strategies.

Main Results:

• The receptor-based MFA model demonstrated superior predictive performance compared to least squares and pharmacophore-based models.
• Key structural and electronic properties influencing inhibitory activity were elucidated.
• Specific substituent effects contributing to potent inhibition were identified.

Conclusions:

• The developed 3D-QSAR models provide valuable insights into the structure-activity relationships of TMPK inhibitors.
• The findings guide the design of novel, potent antitubercular agents targeting Mycobacterium tuberculosis.
• This research contributes to the ongoing efforts to combat tuberculosis through rational drug design.