New insights into binding of natural chalcones to Bcl-2, Bcl-xL and Mcl-1 anti-apoptotic proteins

Knowledge about mechanisms responsible for induction of tumor cell apoptosis is important for the development of anticancer drugs. Mounting evidence suggests that the inhibition of anti-apoptotic proteins of Bcl-2 family is important part of antitumor activity of natural chalcones. In order to gain insights into their binding affinity and binding mechanism, the MM-GBSA binding energies were determined for 63 natural chalcones to Bcl-2, Bcl-xL and Mcl-1, by employing multiple crystal structures of each antiapoptotic protein. It was noticed that the chalcones have high affinity to the BH3-binding groove. The driving forces behind the binding and the anchor points on the proteins were determined for the top ranked chalcones, whereas the 30 0-ns Molecular Dynamics (MD) simulations provided more insights into the binding in the most stable complexes. The importance of ring A, ring B and the side chains of the chalcones for the interactions with the hydrophobic cavities of anti-apoptotic proteins was noticed. Although the natural compounds showed mainly favorable pharmacokinetic properties, some limitations in binding to the proteins, compared to the synthetic ligands, were noticed. This pointed out towards possible future directions of chemical modifications of the most potent natural compounds. It is envisioned that the results of this study could be useful for the selection of lead antitumor natural compounds as well as for the design of new synthetic BH3-mimetics. (c) 2021 Elsevier B.V. All rights reserved.