title: Characterizing the dynamics and ligand-specific interactions in the human leukocyte elastase through molecular dynamics simulations.
abstract: The human leukocyte elastase (HLE), a neutrophil serine protease of the chymotrypsin superfamily, is a major therapeutic target for a number of inflammatory diseases, such as chronic obstructive pulmonary disease (COPD). In this work, we present a comparative explicit water molecular dynamics (MD) study on the free and inhibitor-bound HLE. Knowledge of the flexibility and conformational changes induced by this irreversible inhibitor, whether in a prebound stage or covalently bound at the enzyme binding site, encases fundamental biological interest and is particularly relevant to ongoing structure-based drug design studies. Our results suggest that HLE operates by an induced-fit mechanism with direct intervention of a surface loop which is open toward the solvent in the free enzyme and closed while in the presence of the ligand. MM-PBSA free energy calculations furthermore elucidate the energetic contributions to the distinct conformations adopted by this loop. Additionally, a survey of the major contributions to the inhibitor binding free energies was attained. Our findings enforce the need to account for HLE flexibility, whether through the use of MD-generated ensembles of HLE conformations as targets for molecular docking or via sophisticated flexible-docking algorithms. We anticipate that inclusion of the observed HLE dynamic behavior into future drug design methodologies will have a relevant impact in the development of novel, more efficient, inhibitors.
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal. sestacio@ff.ul.pt
authors.forename: Sìlvia G
authors.initials: SG
authors.lastname: Estácio
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
authors.forename: Rita C
authors.initials: RC
authors.lastname: Guedes
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D055550:Protein Stability; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D019272:Leukocyte Elastase