Abstract

Conformational Flexibility in Drug Design of Anti-apoptotic Proteins Inhibitors

Bogdan Iorga, Team Leader, Centre National De La Recherche Scientifique

The proteins belonging to the Bcl-2 family are involved in cell death regulation. Furthermore, the overexpression of Bcl-xL, Bcl-2 or Mcl-1 proteins in many cancers leads to an accumulation of tumour cells and a resistance to chemotherapy. Thus, the development of new compounds targeting this family of proteins is of high priority given the scarcity of efficient drugs in anticancer therapeutics. In our approach, all-atom molecular dynamics simulations of several crystal structures of Bcl-xL and Mcl-1 provided representative conformations for these two anti-apoptotic proteins. Subsequent molecular docking of the natural compound meiogynine A and several of its synthetic derivatives allowed the selection of protein conformations that are able to correctly recognize the active compounds and to discriminate against the inactive ones. An iterative process of i) virtual screening of focused virtual ligand libraries, ii) organic synthesis and iii) biological evaluation led to several compounds with very good activities against both Bcl-xL and Mcl-1.