Protcool: um gerador de protocolos para ancoragens e simulações de dinâmica molecular em complexos proteína-ligante

Abstract

In recent years, a significant evolution in the simulations in molecular dynamics (DM) has been noticed either in the precision of results compared to the real world or in the capacity to represent complex biological systems with thousands or millions of atoms. Despite all the advances in theories, algorithms, and computational infrastructure that give support and confidence to the current simulations, a serious practical issue persists: the reproducibility of experiments. Other concerning aspects are the lack of more standardized protocols, the lack of comprehensive documentation of what has been accomplished. In order to try to contribute to the solution to these challenges, this thesis aimed to develop, configure, structure and verify a tool that seeks the automation of protocols and workflows (called ProtCool) that enables the control, analysis and reproduction of experiments in molecular dynamics of proteins and molecular docking with multiple ligands. To achieve this main objective, it was necessary to go through the following specific objectives: Model and implement the workflow for preparing the molecular dynamics simulation; Model and implement the workflow for performing multi-molecule dockings; Perform workflow management script implementation; Implement the data source tool, allowing the researcher to have all the files and data generated during the simulation preparation; Automate the preparation of molecular dynamics; Run only part of the workflow; Perform the reproducibility of experiments and research methodologies; Integrate all this into a tool called ProtCool; Check the tool with case studies involving docking of ligands with human acetylcholinesterase and major protease (Mpro) from SARS-Cov-2. Human acetylcholinesterase, implicated in diseases such as Alzheimer's disease, and the main protease (Mpro) of SARS-CoV-2, the virus responsible for the current pandemic of the disease COVID-19, were used as targets in case studies for validating and demonstrating the use of the tool. For acetylcholinesterase, the same 4 ligands (galantamine, lycoramine, sanguinine and a hybrid ligand) and target (4EY6) studied by Rocha (2017) were used as a way to validate the implementation of ProtCool, producing equivalent results. As a way of indicating the potential use of ProtCool in the virtual screening of ligands on a large scale, in a relevant and current problem, the molecular docking of multiple ligands (19637 from ZINC, 8752 form Drugbank, and 8520 from SistematX, totaling 36909 ligands) on multiple targets (6 different conformations sampled by Metadynamics) involving the Mpro of SARS-CoV-2 was carried out, resulting in the generation 4427839 poses (using Vina and Smina docking systems). It was possible to show a new in silico strategy to indicate new ligands as candidates for antivirals against COVID19.