Steric Effects

Steric effects — the influence of substituent size and three-dimensional bulk on a molecule's ability to access its target binding site — are probed by...

Steric effects — the influence of substituent size and three-dimensional bulk on a molecule's ability to access its target binding site — are probed by systematically varying substituent size at a defined structural position, revealing the spatial tolerance of the binding pocket at that specific location. A binding site position showing sharply reduced activity upon introduction of even a modestly larger substituent indicates a sterically constrained sub-pocket, information that directly informs which structural positions are suitable targets for further elaboration to improve potency or introduce additional binding interactions, and which must instead be kept minimally substituted to avoid a steric clash that would abolish activity.