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Free Energy Calculations

Method
Method
Method

Free energy calculations are used to estimate changes in free energy associated with molecular processes, such as ligand binding, protein folding, and conformational changes. These calculations are based on the thermodynamics of molecular interactions, which are fundamental for understanding and predicting the stability and affinity of molecular complexes. The Gibbs free energy (that assumes constant pressure, which is appropriate for drug design) can be described in terms of enthalpy and entropy (dG = dH - TdS). A decrease of enthalpy (dH) is associated with stabilization through favorable interactions. This is often paired with a decrease of entropy, which is unfavorable for delta G.

Importance in Computational Drug Discovery

  1. Binding Affinity Prediction: Free energy calculations can predict the binding affinities of ligands to their target, aiding in the identification potential drug candidates.
  2. Lead Optimization: Free energy calculations enable the optimization of lead compounds by predicting binding affinities.
  3. Selectivity and Specificity: These calculations can help in designing drugs with high selectivity and specificity by predicting the binding affinity to homologous targets.
  4. Mechanistic Insights: Accurate free energy calculations require simulations that can offer mechanistic insights into molecular interactions and processes, facilitating the understanding of drug binding.

Key Tools

1. GROMACS: A versatile molecular dynamics package that supports free energy calculations using various methods, including free energy perturbation (FEP) and thermodynamic integration (TI).

2. AMBER: A suite of programs for molecular dynamics simulations, supporting free energy calculations using FEP, TI, and other methods.

3. NAMD: A parallel, object-oriented molecular dynamics code designed for high-performance simulations, supporting free energy calculations.

4. CHARMM: A program for macromolecular simulations, including free energy calculations using FEP, TI, and other methods.

5. FEP+: A specialized tool for performing free energy perturbation calculations, integrated with Schrödinger's molecular modeling suite.

Literature

"Relative Binding Free Energy Calculations in Drug Discovery: Recent Advances and Practical Considerations"    

Publication Date: 2017-12-15    

DOI:10.1021/acs.jcim.7b00564    

Summary: Provides an overview of current relative binding free energy (RBFE) implementations, highlighting recent advances and practical considerations for reliable RBFE results in real-world drug discovery applications."

Alchemical Transformations and Beyond: Recent Advances and Real-World Applications of Free Energy Calculations in Drug Discovery"  

Publication Date: 2024-10-03    

DOI:10.1021/acs.jcim.4c01024    

Summary: Reviews practical applications of free energy perturbation (FEP) in drug discovery projects, emphasizing ligand-centric and residue-centric transformations.

"The Slow but Steady Rise of Binding Free Energy Calculations in Drug Discovery"    

Publication Date: 2022-12-05    

DOI:10.1007/s10822-022-00494-x    

Summary: Discusses the advancements and challenges that have made free energy calculations practical for drug discovery.

"Large-Scale Assessment of Binding Free Energy Calculations in Active Drug Discovery Projects"    

Publication Date: 2020-01-07    

DOI:10.26434/chemrxiv.11364884.v1    

Summary: Presents the results of large-scale prospective application of the FEP+ method in active drug discovery projects at Merck KGaA, comparing results with a benchmark of eight pharmaceutically relevant targets.

"Understanding the Impact of Binding Free Energy and Kinetics Calculations in Modern Drug Discovery"    

Publication Date: 2024-05-09    

DOI:10.1080/17460441.2024.2349149    

Summary: Reviews computational techniques for drug binding free energy and kinetics calculations, highlighting their role in rational drug design.

"Alchemical Binding Free Energy Calculations in AMBER20: Advances and Best Practices for Drug Discovery"    

Publication Date: 2020-09-16    

DOI:10.1021/acs.jcim.0c00613    

Summary: Provides a contemporary overview of scientific, technical, and practical issues in running relative binding free energy simulations in AMBER20 for real-world drug discovery applications.

"Recent Advances in Alchemical Binding Free Energy Calculations for Drug Discovery"    

Publication Date: 2023-02-16    

DOI:10.1021/acsmedchemlett.2c00541    

Summary: Reviews recent applications of binding free energy calculations in solving diverse drug discovery challenges, including fragment growing, scaffold hopping, and virtual screening.

"Recent Developments in Free Energy Calculations for Drug Discovery"    

Publication Date: 2021-08-11    

DOI:10.3389/fmolb.2021.712085    

Summary: Reviews varied methodologies, developments enhancing simulation efficiency, and remaining challenges in free energy calculations for drug discovery.

"Deep Drug Discovery of Mac Domain of SARS-CoV-2 (WT) Spike Inhibitors: Using Experimental ACE2 Inhibition TR-FRET Assay, Screening, Molecular Dynamic Simulations and Free Energy Calculations"    

Publication Date: 2023-08-01    

DOI:10.3390/bioengineering10080961    

Summary: Identifies stable binding poses of lead compounds for SARS-CoV-2 using virtual screening, TR-FRET assay, MD simulations, and free energy calculations.

"Advancing Drug Discovery through Enhanced Free Energy Calculations"    

Publication Date: 2017-07-05    

DOI:10.1021/acs.accounts.7b00083    

Summary: Discusses the methodological advances and applications of free energy calculations in drug discovery, with a focus on the FEP+ approach.