Fabien Fontaine1, Simon Cross, Guillem Plasencia, Manuel Pastor, Ismael Zamora
1Lead Molecular Design, S.L. Av. Cerdanyola 92-94, 08173 Sant Cugat del Vallés, Barcelona, Spain.
Tóm tắt
AbstractWe present a method for fragment/scaffold substitution based on protein–ligand interactions. This concept goes beyond bioisosteric replacement, which only uses the structure of the fragment to replace as query. The methodology is validated with more than 10 biological targets relevant for drug discovery.magnified imageA new method for fragment and scaffold replacement is presented that generates new families of compounds with biological activity, using GRID molecular interaction fields (MIFs) and the crystal structure of the targets. In contrast to virtual screening strategies, this methodology aims only to replace a fragment of the original molecule, maintaining the other structural elements that are known or suspected to have a critical role in ligand binding. First, we report a validation of the method, recovering up to 95 % of the original fragments searched among the top‐five proposed solutions, using 164 fragment queries from 11 diverse targets. Second, six key customizable parameters are investigated, concluding that filtering the receptor MIF using the co‐crystallized ligand atom type has the greatest impact on the ranking of the proposed solutions. Finally, 11 examples using more realistic scenarios have been performed; diverse chemotypes are returned, including some that are similar to compounds that are known to bind to similar targets.
