Le 2 décembre 2016, 10:58 dans Humeurs • 0
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The interaction of a protein with endogenous ligands is at the heart of developing new chemotherapeutic agents; emulating how a ligand binds within a known target macromolecular active site is essential to drug discovery. In the following work, several aspects of drug design are enlightened, including structural-based drug design, structural determination and binding interface identification, and fragment-based drug discovery (FBDD). Primarily is the proposal of a new anti-viral drug candidate for the Influenza A virus, which is a structural-based drug design project employing a carbon-sulfur atom switch. This allows for a more suitable fit in the molecular space allotted in the binding site provided by the known target, the matrix 2 (AM2) proton channel. Understanding how the adamantanes interact with the binding site was essential in the design of this proposed drug candidate, 2,4,9-trithiaadamante-7-amine. Another aspect of drug design is the structural identification of a target, as seen in the second project; the work investigates epigenetic changes and how they occur via interactions between a known long non-coding RNA (lncRNA), the steroid receptor activator (SRA) RNA and the RNA recognition motif (RRM) 1 of the SMRT/HDAC1 Associated Repressor Protein SHARP with the distant objective of developing a small molecule chemotherapeutic agent. This involves the solution structure determination of SHARP1P82*, with the determination of the binding interface between the domain and the region of SRA RNA stem loop region 7 (STR7).
Lastly, an FBDD project is explored using the glutaredoxin protein system as the known target. The ortholog glutaredoxins, human glutaredoxin 1 (hGRX), and bacterial Brucella melitensis (brmGRX) and Pseudomonas aergunisa (paGRX) are essential proteins with anti-oxidative roles. There are several health risks involving these proteins and the misbalance of the redox system, including Brucella ovis (Malta fever), and cystic fibrosis (CF). Fragments optimization with the goal of developing a small molecule selective inhibitor is an essential aspect to FBDD. The scope of the research spans several phases of the process of drug discovery, from structural-based drug design to the structural determination of the binding target site, and lastly, to insights into the rapid growth of drug design via FBDD methods.