Progress in Free Energy Perturbation: Options for Evolving Fragments.

Area of Science:

• Computational chemistry
• Drug discovery
• Molecular modeling

Background:

• Fragment-based drug design (FBDD) faces challenges in optimizing initial hit fragments.
• Computational methods are increasingly used to predict binding affinity for novel analogues.
• Alchemical free energy (AFE) calculations offer high accuracy for lead optimization.

Purpose of the Study:

• To review the application of alchemical free energy calculations in fragment-based drug design.
• To highlight the potential impact of AFE on fragment evolution strategies.
• To identify and discuss challenges associated with using AFE in FBDD.

Main Methods:

• Review of existing literature on alchemical free energy calculations in drug design.
• Analysis of AFE's role in fragment-based lead discovery and optimization.
• Discussion of computational methodologies and their integration into FBDD workflows.

Main Results:

• AFE calculations demonstrate potential for accurate binding affinity prediction.
• AFE can significantly guide the optimization of fragment hits.
• Challenges exist in applying AFE, particularly concerning computational cost and accuracy for diverse fragments.

Conclusions:

• Alchemical free energy calculations show promise for accelerating fragment evolution in FBDD.
• Addressing computational challenges is crucial for widespread AFE adoption in FBDD.
• Further research is needed to optimize AFE methodologies for fragment-based lead optimization.