Perspective on the SAMPL and D3R Blind Prediction Challenges for Physics-Based Free Energy Methods

Kartograf: A Geometrically Accurate Atom Mapper for Hybrid-Topology Relative Free Energy Calculations

“…Drug design is a complex process that necessitates balancing cost, speed, and accuracy to achieve efficiency. , In recent years, in silico methods have become increasingly important in enhancing these factors. ,− A fundamental property in the multifaceted drug design process is potency, alongside ADME and synthetic accessibility. ,− To evaluate the potency of potential drug candidates in silico, free energy calculation methods, including simulations on the theoretical level of molecular mechanics or quantum mechanics, are currently the state-of-the-art that promise the most accurate estimates. , Furthermore, large efforts are undertaken to automatize such approaches. − In order to rank the most promising drug candidates by potency with in silico methods, ligands are typically ranked based on their calculated binding free energies. , …”

Modern Alchemical Free Energy Methods for Drug Discovery Explained

“…176,177 As the methods evolve to meet these and other challenges, it will become increasingly important to perform large-scale assessments 178,179 and conduct community-wide blind challenges. 180,181 Emerging technologies that promise to improve the accuracy and precision of AFE calculations in drug discovery include the development of end-state ensemble reservoirs that can be used within networks to ensure consistent end states as well as continued evolution of sampling methods. Finally, there are a number of exciting advances in the development of new force fields that promise higher levels of accuracy, most notably classical polarizable force fields 182−186 and machine learning potentials (MLPs).…”

“…There are a vast number of outstanding issues that are being actively addressed by a variety of groups at the forefront of the field. Some selected for mention here include the following: Methods to handle interfacial and buried (kinetically trapped) water molecules that can fluctuate in occupancy upon binding. − Charge-changing ligand perturbations and counterbalancing salt effects. − Alternative tautomers , and protonation states of both ligand and target molecules. ,, Binding sites involving metal–ligand interactions. , Covalent inhibition. , As the methods evolve to meet these and other challenges, it will become increasingly important to perform large-scale assessments , and conduct community-wide blind challenges. , …”

“… 177 , 178 As the methods evolve to meet these and other challenges, it will become increasingly important to perform large-scale assessments 179 , 180 and conduct community-wide blind challenges. 181 , 182 …”

Energy-entropy multiscale cell correlation method to predict toluene–water log P in the SAMPL9 challenge

“…27 To help assess the accuracy and capabilities of different computational methods, the SAMPL (statistical assessment of the modelling of proteins and ligands) log P blind challenges have helped demonstrate the performance of computational methods. 28 Previously they involved water with octanol or cyclohexane solvent. Now in the ninth running, the SAMPL9 log P challenge involves the less commonly used toluene-water log P [6][7][8][9][10][11][12] for the drug molecules depicted in Fig.…”