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Item Estudio estructural del rol inhibitorio de derivados de naftaleno frente a la enzima Plpro de SARS-CoVAutores: Castillo Campos, Luis AndrésAutor Institucional: Universidad de TalcaProfesor Informante: Vergara Jaque, ArielaProfesor Tutor: Caballero Ruiz, Julio; Velásquez Libera, José LuisLa proteasa SARS-CoV PLpro está asociada a diferentes funciones que ocasionan el antagonismo de la respuesta inmune innata antiviral del huésped, como lo es la deubiquitinación y la desISGilación de las proteínas de las células de este. Dada la función que desempeña, la atención en la PLpro como diana terapéutica para el diseño de fármacos contra el SARS-CoV, MERS-CoV y actualmente el SARS-CoV-2, ha ido en aumento y se han reportado compuestos candidatos para detener la actividad de esta enzima. Entre estos, se reportó un conjunto de inhibidores no covalentes basados en naftaleno, que incluye compuestos que muestran una alta capacidad inhibitoria contra la PLpro de SARS-CoV. La comprensión de las características estructurales que facilitan la interacción entre la PLpro de coronavirus y sus ligandos es de gran utilidad para entender el funcionamiento de esta enzima y su capacidad para ser intervenida con inhibidores más efectivos. En este trabajo se revelaron características estructurales de los derivados del naftilo que explican su actividad contra la enzima PLpro de SARS-CoV, a través de un estudio detallado de las interacciones ligando-receptor. El protocolo empleado se inició con el método docking molecular, el cual permitió considerar las orientaciones de los ligandos en el sitio de unión de la proteasa. Posterior a ello, se realizaron diversos análisis quimiométricos: se utilizó el servidor LigRMSD para comparar las orientaciones de los inhibidores estudiados, se realizó un análisis de huellas de interacción para describir las interacciones recurrentes entre los residuos de la proteína y los grupo del ligando en los complejos y finalmente se construyeron modelos 3D-QSAR para explicar la relación entre la estructura de los compuestos y su actividad inhibitoria. Se describieron las interacciones entre diferentes porciones del ligando y varios residuos claves (Asp165, Tyr269, Gln270 y Tyr265), además de la ocupación de estos inhibidores en los subsitios S3 y S4 de la proteasa. Se encontró que la serie de compuestos derivados del naftaleno adoptan orientaciones similares en el sitio de unión de PLpro, con una alta semejanza con las orientaciones de los ligandos co-cristalizados. Sumado a esto, los modelos 3D-QSAR construidos en base a diferentes estrategias de alineamiento, no cumplieron en su totalidad con los requisitos estadísticos para ser considerados modelos con alto poder predictivo. En base a estos resultados, se propone el uso de una nueva metodología para explicar la actividad biológica de la serie de inhibidores. // ABSTRACT: The SARS-CoV protease PLpro is associated with different functions that cause antagonism of the host innate antiviral immune response, such as deubiquitination and deISGylation of host cell proteins. Given the role it plays, attention on PLpro as a therapeutic target for the design of drugs against SARS-CoV, MERS-CoV and currently SARS-CoV-2, has been increasing and candidate compounds have been reported to reduce the activity of this enzyme. Studying the structural features that facilitate the interaction between coronavirus PLpro and its ligands is of great utility in understanding the functioning of this enzyme and its ability to be targeted with more effective inhibitors. In this work, structural features of naphthyl derivatives against SARS-CoV PLpro enzyme were revealed through a detailed study of ligand-receptor interactions. The protocol started with the molecular docking method, which allowed to consider the ligand orientations at the protease binding site. Subsequently, several chemometric analyses were performed: the LigRMSD server was used to compare the orientations of the studied inhibitors, an interaction fingerprint analysis was performed to describe the recurrent interactions between the protein residues and the ligand groups in the complexes; finally, 3D-QSAR models were constructed to explain the relationship between the structure of the compounds and their inhibitory activity. The interactions between different portions of the ligand and key residues (Asp165, Tyr269, Gln270 and Tyr265) were described, in addition to the occupancy of these inhibitors at the S3 and S4 sub-sites of the protease. It was found that the serie of naphthalene-derived compounds adopted similar orientations at the PLpro binding site, with high similarity to the orientations of co-crystallized ligands. In addition, the 3D-QSAR models constructed based on different alignment strategies did not fully meet the statistical requirements to be considered models with high predictive power. Based on these results, a new methodology is proposed to explain the biological activity of the inhibitor series.Item Computational study of the binding orientation and affinity of noncovalent inhibitors of the papain-like protease (PLpro) from SARS-CoV-1 considering the protein flexibility by using molecular dynamics and cross-dockingAutores: Castillo Campos, Luis Andrés; Velázquez Libera, José Luis; Caballero Ruíz, Julio MiguelThe papain-like protease (PLpro) from zoonotic coronaviruses (CoVs) has been identified as a target with an essential role in viral respiratory diseases caused by Severe Acute Respiratory Syndrome-associated coronaviruses (SARS-CoVs). The design of PLpro inhibitors has been proposed as an alternative to developing potential drugs against this disease. In this work, 67 naphthalene-derived compounds as noncovalent PLpro inhibitors were studied using molecular modeling methods. Structural characteristics of the bioactive conformations of these inhibitors and their interactions at the SARS-CoV-1 PLpro binding site were reported here in detail, taking into account the flexibility of the protein residues. Firstly, a molecular docking protocol was used to obtain the orientations of the inhibitors. After this, the orientations were compared, and the recurrent interactions between the PLpro residues and ligand chemical groups were described (with LigRMSD and interaction fingerprints methods). In addition, efforts were made to find correlations between docking energy values and experimentally determined binding affinities. For this, the PLpro was sampled by using Gaussian Accelerated Molecular Dynamics (GaMD), generating multiple conformations of the binding site. Diverse protein conformations were selected and a cross-docking experiment was performed, yielding models of the 67 naphthalene-derived compounds adopting different binding modes. Representative complexes for each ligand were selected to obtain the highest correlation between docking energies and activities. A good correlation (R2 = 0.948) was found when this flexible docking protocol was performed.
