Inhibition of Antiapoptotic BCL-XL, BCL-2, and MCL-1 Proteins by Small Molecule Mimetics

Abstract

Informatics and computational design methods were used to create new molecules that could potentially bind antiapoptotic proteins, thus promoting death of cancer cells. Apoptosis is a cellular process that leads to the death of damaged cells. Its malfunction can cause cancer and poor response to conventional chemotherapy. After being activated by cellular stress signals, proapoptotic proteins bind antiapoptotic proteins, thus allowing apoptosis to go forward. An excess of antiapoptotic proteins can prevent apoptosis. Designed molecules that mimic the roles of proapoptotic proteins can promote the death of cancer cells. The goal of our study was to create new putative mimetics that could simultaneously bind several antiapoptotic proteins. Five new small molecules were designed that formed stable complexes with BCL-2, BCL-XL, and MCL-1 antiapoptotic proteins. These results are novel because, to our knowledge, there are not many, if any, small molecules known to bind all three proteins. Drug-likeness studies performed on the designed molecules, as well as previous experimental and preclinical studies on similar agents, strongly suggest that the designed molecules may indeed be promising drug candidates. All five molecules showed "drug-like" properties and had overall drug-likeness scores between 81% and 96%. A single drug based on these mimetics should cost less and cause fewer side effects than a combination of drugs each aimed at a single protein. Computer-based molecular design promises to accelerate drug research by predicting potential effectiveness of designed molecules prior to laborious experiments and costly preclinical trials.

Keywords: anticancer drug research; apoptosis; cancer; small molecule mimetics.

Figure 1.

Structures of the five designed small molecules, from left to right: C₁₈H₂₃N₄, C₁₆H₁₅N₆, C₁₄H₁₅N₃O, C₁₇H₁₅N₄, and C₁₃H₁₀N₃. Color code: C-yellow, N-pink, O-green, H-white.

Figure 2.

The MCL-1 binding groove is shown with designed small molecule C₁₇H₁₅N₄ (red ball-and-stick). MCL-1 residues that bind Noxa and Puma, M212, V230, V234, T247, and F251, are shown as yellow solid spheres. Nearby MCL-1 residues are presented as purple solid spheres. To increase visibility of the small molecule and yellow residues, some MCL-1 residues are either presented as purple ball-and-stick or omitted.