In silico evaluation of bioactive compounds: Docking Simulations based Enzyme-Inhibitor Interaction compared with X-ray models

摘要

Modern drug design approaches are based on accurate prediction of the protein-ligand binding interface and binding properties/modes of the ligand, even if experimentally determined (through X-ray or NMR) protein-ligand complex model is not available. The knowledge of the structure and physicochemical determinants of protein-substrate recognition- and binding is of fundamental importance in structure-based drag design. What is highlighted herein is the procedure which makes use of tools of bioinformatics in order to test the binding properties of a ligand to a biomacromolecule. Since our research activities oriented in the quest of bioactive compounds as inhibitors towards zinc metallopeptidases, such us Angiotensin-1 Converting Enzyme (ACE) and Anthrax Lethal Factor (ALF), we are studying the enzyme's catalytic sites and/or inhibitors conformational characteristics through Nuclear Magnetic Spectroscopy (NMR). Furthermore, we exploit the acquired structural data in an attempt to screen various compounds according their binding affinity in silico, through docking simulations methodology. Possible lead compounds will be optimized, synthesized and their binding properties would be then determined experimentally (using Xray or NMR). In this procedure application of docking simulations approaches is a prerequisite and the evaluation of the binding modes of a ligand to a protein target should be performed. To this effect, we implement docking simulations to the study of enzyme-inhibitor complexes and the results are compared to already known enzyme-inhibitor crystal structures. The potential for a docking algorithm to be used as a virtual screening tool is based on both speed and accuracy .