Abstract

This research focuses on computational molecular design for possible anticancer applications. Computer-based design is an interdisciplinary field which draws on computer science, biophysics, engineering, and biochemistry. It has sped up research by decreasing the need for often expensive and time-consuming experiments. Programmed cell death (apoptosis) is an essential cellular process. Its malfunction can cause cancer and other diseases. Proteins that regulate apoptosis can be either pro-death or pro-survival. Pro-death protein Noxa binds pro-survival protein Mcl-1 and allows apoptosis to proceed. Cells with overexpressed Mcl-1 do not respond properly to Noxa and resist apoptosis, leading to resistance to conventional cancer therapies. Mimetics are designed molecules, which mimic the function of cell proteins. Noxa mimetics were computationally designed to bind Mcl-1, and thus allow apoptosis. Experimental Noxa structure was used as a template to design putative peptide mimetics in Deep View program. Mcl-1 made the most stable complex with peptide Ala-Glu-Asp-Pro-Pro-Glu-Phe, with the binding energy of -4.8 kcal/mol. Putative small-molecule mimetics were designed in ArgusLab program. Mimetics C₃₂H₁₆N₁₀ and C₃₂H₁₆QN₁₀ (Q = Ga, N, P, S, Se) made stable complexes with Mcl-1, but also with pro-survival proteins Bfl-1 and Bcl-w. A drug based on these mimetics may be useful in fighting cancers with multiple overexpressed pro-survival proteins. A single drug would likely be more economical and better tolerated by patients than several drugs targeting individual proteins. Experimental studies are needed to determine the utility of the putative mimetics for clinical applications. Computational drug design is a rapidly developing field that has a vast potential to enable drug design to ultimately treat almost any illness.