title: Predicting Binding Free Energies: Frontiers and Benchmarks.
abstract: Binding free energy calculations based on molecular simulations provide predicted affinities for biomolecular complexes. These calculations begin with a detailed description of a system, including its chemical composition and the interactions among its components. Simulations of the system are then used to compute thermodynamic information, such as binding affinities. Because of their promise for guiding molecular design, these calculations have recently begun to see widespread applications in early-stage drug discovery. However, many hurdles remain in making them a robust and reliable tool. In this review, we highlight key challenges of these calculations, discuss some examples of these challenges, and call for the designation of standard community benchmark test systems that will help the research community generate and evaluate progress. In our view, progress will require careful assessment and evaluation of new methods, force fields, and modeling innovations on well-characterized benchmark systems, and we lay out our vision for how this can be achieved.
authors.affiliation: Department of Pharmaceutical Sciences and Department of Chemistry, University of California, Irvine, California 92697; email: dmobley@mobleylab.org.
authors.forename: David L
authors.initials: DL
authors.lastname: Mobley
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences and Center for Drug Discovery Innovation, University of California, San Diego, La Jolla, California 92093; email: mgilson@ucsd.edu.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Gilson
mesh_terms: D019985:Benchmarking; D001952:Bridged-Ring Compounds / Q000737:chemistry; D003198:Computer Simulation; D055808:Drug Discovery / Q000379:methods; D007093:Imidazoles / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D009113:Muramidase / Q000737:chemistry; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D012984:Software; D013816:Thermodynamics; D047028:Macrocyclic Compounds; D000099246:Cucurbit(n)urils
chemical_list: D001952:Bridged-Ring Compounds; D007093:Imidazoles; D008024:Ligands; D009113:Muramidase; D011506:Proteins; C456276:cucurbit(7)uril; D047028:Macrocyclic Compounds; D000099246:Cucurbit(n)urils
keywords: alchemical; benchmark; binding affinity; binding free energy; biomolecular interactions; molecular simulation