Surprising Non-Additivity of Methyl Groups in Drug–Kinase Interaction

Positional Analogue Scanning: An Effective Strategy for Multiparameter Optimization in Drug Design

“…Various manifestations of positional analogue scanning have been reported in the literature for decades, variably described as an atom or substituent scan, transposition, shift, walk, dance, or shuffle, generally constituting a partial scan of a single aromatic or heteroaromatic ring of a polycyclic drug molecule, and typically focused on a single pharmacological parameter, such as potency. , It is recommended in this Perspective that a generic term, positional analogue scanning, be used to describe this general strategy, as positional analogue scanning in small molecule drug discovery is analogous to alanine scanning in polypeptide biochemical studies and both are intended to be systematic and complete. , The maximal value of positional analogue scanning can be realized by assessment of negative, neutral, or positive impacts across multiple pharmacological parameters, exploring all possible positional analogues in situations where predictive modeling is not available. , Additionally, positional analogue scanning can provide opportunities to identify activity cliffs and nonadditive SAR that may elucidate ligand binding conformations and receptor binding modes . The modern need in chemical biology and drug discovery for rapid and simultaneous multiparameter optimization justifies the synthesis investment that may be required to enable full positional analogue scanning.…”

Two Methods, One Goal: Structural Differences between Cocrystallization and Crystal Soaking to Discover Ligand Binding Poses

“…Cocrystal structures of 1 and 3 – 7 have been documented in previous contributions [23,24,29] . The corresponding soaked structures were collected at the storage ring Bessy II Helmholtz‐Zentrum Berlin, Germany at Beamline 14.1 on a Pilatus 6 M pixel detector.…”

“…The cocrystallization protocols of 1 , 3 – 7 were discussed previously [23,24,29] . Thus, only differences to the soaking protocols will be reported here.…”

Hydration-Induced Disorder Lowers the Energy Barriers for Methyl Rotation in Drug Molecules

“…33 On the contrary, the interaction between the solvent and small-molecule ligands is common and can play a significant role in ligand−protein binding, e.g., a flexible ligand entraps water molecules in solution before binding to a protein and by the release of these water molecules achieves the favored entropic binding. 34 For the methyl groups introduced to drug molecules to improve the interaction between the drugs and targeted protein, it has been recently demonstrated 29 that a reliable analysis of the binding cannot rely on the static crystallographic modeling but must explicitly consider the interactions of methyl groups with the solvent using MD. Those conclusions, showing direct importance for the drug−target binding of the methyl−solvent interaction and the resulting effect of the changing energy barriers experienced by the methyl groups, could be equally applicable to the drugs investigated herein.…”

“…Importantly, this effect on the potential barriers is not merely steric, as the activation energy for methyl group rotations decreases much below the intrinsic values characteristic of an isolated drug molecule and must be caused by methyl–water interaction. Therefore, analogously to the recently published study of the effect of methyl groups on drug-kinase interaction, a reliable analysis of the thermodynamics of binding of the drugs studied herein to their target molecules cannot rely solely on the static crystallographic modeling but must explicitly consider the interactions of methyl groups with the solvent, as well as their interplay in the dynamical processes of the methyl rotation.…”