Le Jeudi 26 Avril 2018 16:50 CEST, WENHE ZHONG <wenhezhong.xmu....@gmail.com> a écrit:
Just to be sure: how was the nM affinity evaluated ? By in vitro measurements, or by obtaining an IC50 by tests on cells ? Of course, if you are mentioning an IC50, you may have a measurement of the efficacy of drug entrance in the cells, not just of specific binding to your protein target. Philippe D. > Dear Community, > > A little bit out of topic here. We are applying the structure-based approach > to design compounds that can bind our protein target. We have synthesized a > series of analogues based on the same scaffold with different substituents at > one particular site. The most potent analogue (nM Kd) has a long alkyl chain > substituent. We thought this hydrophobic substituent should have strong > interactions with the target protein leading to nM range affinity. However, > crystal structures show very weak densities for this substituent and no > obvious interaction between the substituent and the target protein, > suggesting that this long alkyl chain substituent is flexible without binding > to the protein. This binding site is relatively negative charged according to > the electrostatic potential analysis. > > So it is a puzzle to me that how this dynamic and hydrophobic alkyl chain > substituent can lead the compound to achieve nM affinity (>10-fold better > than any other substituent) — in particular the binding site is not > hydrophobic and no interaction is found between the substituent and the > protein. > > Anything I have miss here that can increase the binding affinity without > interacting with the target? > > Thanks. > > Kind regards, > Wenhe > > >
