Protonation states and conformational ensemble in ligand-based QSAR modeling

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Drug Discovery

Background:

• Drug affinity and function are significantly influenced by varying protonation states within biological systems.
• Different protonation species lead to distinct molecular conformations, affecting physico-chemical properties and biological activity.

Purpose of the Study:

• To review the critical role of interdependent structural features, driven by protonation states, in ligand-based quantitative structure-activity relationship (QSAR) modeling.
• To highlight the application of quantum chemical descriptors and molecular shape analysis in understanding these relationships for drug design.

Main Methods:

• Utilizing quantum chemical electronic and reactivity descriptors.
• Employing molecular shape description techniques.
• Analyzing computed descriptors on bioactive protonation states and conformers.

Main Results:

• Demonstrated the crucial role of molecular descriptors computed on specific protonation states and conformers.
• Illustrated how these descriptors act as determinant factors in mechanistic/causative QSAR analysis.
• Provided selected examples showcasing the practical application of these methods.

Conclusions:

• Protonation states and resulting conformational ensembles are critical determinants of drug behavior.
• Quantum chemical descriptors and molecular shape analysis of bioactive protonation states are essential for accurate QSAR modeling and rational drug design.