Design of Anticancer Pharmaceutical Compounds Using Structure and Energetics of Lead – Target Interaction(2/3)

Design of pharmaceuticals is an essential part of human fight against various diseases. However, drug design is a multi-step and very complex process. In the first phase, the natural or synthetic compounds are discovered or identified that bind a human target protein responsible for the progression of the illness. Unfortunately, the cost of drug design has risen tremendously but the number of drugs brought to market has not grown significantly.One of the major difficulties in drug design is poor scientific understanding of protein – ligand (drug) interactions. There is no way to predict which compound would bind to which protein and with what affinity. Instead, pharmaceutical industry performs high-throughput screening of all available compounds against a particular disease target and selects the hit compounds for development into drugs. Such compounds usually bind to numerous non-intended targets thus exhibiting numerous toxicity side effects.In this proposal we combine the efforts and experience of three teams, Latvian, Lithuanian and Taiwanese in the areas of organic synthesis, recombinant protein target production and thermodynamics of protein – target interaction, respectively.The objectives of the project are: The Latvian team will design and synthesize compounds which would bind specifically and with average or high affinity to an intended target, namely, histone deacetylases (HDACs), matrix metalloproteinases (MMPs) and carbonic anhydrases (CAs). The Lithuanian team will clone, express in bacterial or human cells and purify the target proteins. Taiwanese team will experimentally determine the energies of compound binding to the three target protein groups by isothermal titration calorimetry to measure the enthalpies, entropies and the Gibbs free energies. They will also develop novel protocols and approaches to prepare compounds with better binding properties and develop the theory of thermodynamic data application for the structure-thermodynamics correlation. In addition, Lithuanian team will determine the Gibbs free energies of compound binding by the inhibition of enzymatic activity (IC50) and the fluorescent thermal shift assay for the selected best lead compounds in order to help rank the compounds for their SAR analysis.The project is possible only by combining the efforts of all three teams and the achievement of the objectives would significantly advance both the fundamental science in the area of energetics of molecular interactions and the application of inhibitors for further development into drugs. As an outcome of the project would be several lead compounds to be outlicensed to pharmaceutical companies for the development into drugs against cancer, inflammation, glaucoma and several other illnesses.