Broadening the Scope of Binding Free Energy Calculations Using a Separated Topologies Approach

Area of Science:

• Computational chemistry
• Drug discovery and design
• Molecular modeling

Background:

• Binding free energy calculations are crucial for predicting drug potency.
• Traditional relative binding free energy (RBFE) methods require similar ligand scaffolds and binding modes, limiting their application.
• Absolute binding free energy (ABFE) calculations can handle diverse ligands but suffer from long convergence times.

Purpose of the Study:

• To introduce and evaluate Separated Topologies (SepTop), a novel RBFE method.
• To enable accurate binding free energy calculations for ligands with significant structural differences, including core hopping.
• To achieve convergence times comparable to traditional RBFE while enhancing flexibility.

Main Methods:

• SepTop performs two simultaneous absolute free energy calculations in opposite directions, one for each ligand.
• This method defines ligands independently, avoiding constraints of identical poses or atom-atom mapping.
• It bypasses the need to sample the unbound protein state, improving efficiency over ABFE.

Main Results:

• SepTop successfully enabled large scaffold changes between ligands.
• The method demonstrated convergence times comparable to traditional RBFE calculations.
• Accuracy was sufficient for rank-ordering ligands, comparable to established RBFE methods.

Conclusions:

• SepTop offers a flexible and accurate alternative for RBFE calculations, suitable for complex drug design scenarios.
• The method overcomes key limitations of existing RBFE and ABFE approaches.
• SepTop provides practical insights for industrial drug design applications, enhancing the prioritization of novel drug candidates.