Prioritizing Small Sets of Molecules for Synthesis through in‐silico Tools: A Comparison of Common Ranking Methods. (29th November 2022)

• Record Type: Journal Article
• Authors: Breznik, Marko; Ge, Yunhui; Bluck, Joseph P.; Briem, Hans; Hahn, David F.; Christ, Clara D.; Mortier, Jérémie; Mobley, David L.; Meier, Katharina
• Is Part Of: ChemMedChem. Volume 18:Number 1(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-11-29
• Subjects: docking -- FEP -- MMGBSA -- drug design -- molecular modelling; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202200425
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: Prioritizing molecules for synthesis is a key role of computational methods within medicinal chemistry. Multiple tools exist for ranking molecules, from the cheap and popular molecular docking methods to more computationally expensive molecular‐dynamics (MD)‐based methods. It is often questioned whether the accuracy of the more rigorous methods justifies the higher computational cost and associated calculation time. Here, we compared the performance on ranking the binding of small molecules for seven scoring functions from five docking programs, one end‐point method (MM/GBSA), and two MD‐based free energy methods (PMX, FEP+). We investigated 16 pharmaceutically relevant targets with a total of 423 known binders. The performance of docking methods for ligand ranking was strongly system dependent. We observed that MD‐based methods predominantly outperformed docking algorithms and MM/GBSA calculations. Based on our results, we recommend the application of MD‐based free energy methods for prioritization of molecules for synthesis in lead optimization, whenever feasible. Abstract : Multiple physics‐based methods exist for ranking compounds using their predicted affinity. We probed the ranking ability of these methods against sixteen pharmaceutically relevant targets with a total of 423 known binders. Our results show that, despite system dependency, MD‐based free energy methods should be used for prioritization whenever feasible.