Optimizing ligand conformations in flexible protein targets: amulti-objective strategy
Finding the orientation of a ligand (small molecule) with the lowest binding energy to the macromolecule (receptor) is a complex optimization problem, commonly called ligand–protein docking. This problem has been usually approached by minimizing a single objective that corresponds to the final free...
| Authors: | , , , , |
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| Format: | article |
| Status: | Versión enviada para evaluación y publicación |
| Publication Date: | 2020 |
| Country: | España |
| Institution: | Universidad de Sevilla (US) |
| Repository: | idUS. Depósito de Investigación de la Universidad de Sevilla |
| OAI Identifier: | oai:idus.us.es:11441/108857 |
| Online Access: | https://hdl.handle.net/11441/108857 https://doi.org/10.1007/s00500-019-04575-2 |
| Access Level: | Open access |
| Keyword: | Molecular Docking Multi-objective optimization Metaheuristics |
| Summary: | Finding the orientation of a ligand (small molecule) with the lowest binding energy to the macromolecule (receptor) is a complex optimization problem, commonly called ligand–protein docking. This problem has been usually approached by minimizing a single objective that corresponds to the final free energy of binding. In this work, we propose a new multiobjective strategy focused on minimizing: (1) the root mean square deviation (RMSD) between the co-crystallized and predicted ligand atomic coordinates, and (2) the ligand–receptor intermolecular energy. This multi-objective strategy provides the molecular biologists with a range of solutions computing different RMSD scores and intermolecular energies. A set of representative multi-objective algorithms, namely NSGA-II, SMPSO, GDE3 and MOEA/D, have been evaluated in the scope of an extensive set of docking problems, which are featured by including HIV-proteases with flexible ARG8 side chains and their inhibitors. As use cases for biological validation, we have included a set of instances based on new retroviral inhibitors to HIV-proteases. The proposed multi-objective approach shows that the predictions of ligand’s pose can be promising in cases in which studies in silico are necessary to test new candidate drugs (or analogue drugs) to a given therapeutic target. |
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