Design of anticancer pharmaceutical compounds using structure and energetics of lead – target interactions

Taivana

Call: Mutual fund Taiwan – Latvia – Lithuania, 2015
Implementation period: 01.04.2016. – 31.03.2019.
Project partners:
National Central University, Taiwan
Latvian Institute of Organic Synthesis, Latvia
Vilnius University, Lithuania
Leader of Latvian team: Dr.chem. Pēteris Trapencieris
Total costs: 204 508  EUR
Costs for Latvian partner: 68 169 EUR

Summary

Rational drug design begins with the phase of discovering lead compounds that strongly interact with target proteins and could be modified, improved and developed into pharmaceuticals. Epigenetic targets are currently considered as one of the most exciting biological target areas to be tackled with drugs against numerous diseases.
Epigenetic mechanisms are inheritable factors that regulate genetic expression and chromatin architecture without changing the DNA sequence. These factors are DNA methylation, histones modifications (methylation, acetylation and phosphorylation), activity of various non histones proteins that bind to the DNA and small regulatory RNAs. Epigenetic enzymes regulate histones and DNA changes by these simple chemical modifications and determine whether genes are turned on or off, and deregulation of the processes plays a central role in several diseases.
Numerous studies have shown the efficacy of epigenetic drugs in hematologic malignancies and several more are showing that epigenetic drugs when used in combination with anti-cancer drugs are driving solid tumor treatment. According to the Structural Genomics Consortium, there are 377 known epigenetic targets. But epigenetics has so far yielded only four approved drugs.
The three research teams of this project have combined their efforts to improve the knowledge of protein – drug recognition and to make compounds that would be proposed to develop as drugs primarily against cancer. All three teams have significant experience and continue to use the target-based drug discovery approach. Protein targets will be a part of the epigenetic proteins, mostly metalloenzymes containing zinc in their active site. Metalloenzymes are widely distributed in human body and their loss of activity or misregulation causes numerous diseases.
Choosing similar target proteins helps by grouping the compounds to a limited set of pharmacophore groups that would bind to a particular set of targets. For example, aromatic primary sulfonamides are widely known to tightly and specifically bind and inhibit carbonic anhydrases (CAs). Similarly, hydroxamic acid-containing compounds recognize and bind one group of zinc-containing histone deacetylases (HDACs), a class of epigenetically modifying enzymes.
The consortium proposes to design, synthesize new eventually active compounds and to develop methodology for their activity screening by calorimetry methods. The mechanisms of action would be tsted by the X-ray structure studies to develop further more active compounds. All the planned activities logistically follow each other and the new results may optimize the process of development of leading structures.