Targeting proteins with halogenated drugs: new strategies to probe halogen-bonding hotspots

Detalhes bibliográficos
Autor(a) principal: Henriques, Bernardo Miguel Vagarinho
Data de Publicação: 2020
Tipo de documento: Dissertação
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10451/47979
Resumo: Tese de mestrado, Química (Química) Universidade de Lisboa, Faculdade de Ciências, 2020
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spelling Targeting proteins with halogenated drugs: new strategies to probe halogen-bonding hotspotsligação de halogéneos-holehotspots de ligação de halogéneoAutoDock VinaXBdocking molecularTeses de mestrado - 2020Departamento de Química e BioquímicaTese de mestrado, Química (Química) Universidade de Lisboa, Faculdade de Ciências, 2020The incorporation of halogens (X) in drug molecules is a common strategy used to enhance drug ADME (absorption, distribution, metabolism, and excretion) properties, often leading to increased potency. In addition to that, halogen atoms are usually perceived as a negatively-charged species, only capable of interacting with electrophiles (E), for instance, through hydrogen bonds. However, when an halogen atom is covalently-bound (R–X, X = Cl, Br, I), its electron density is anisotropically distributed, possessing a positive region at the tip of X, designated as s-hole. Consequently, electron rich species such as a lone pair of a Lewis base (B), can interact with the positive s-hole of a covalently-bound halogen (R–X_ _ _ B), establishing an halogen bond (HaB). HaBs are becoming increasingly important and have been successfully used in multiple fields, such as supramolecular chemistry, anion recognition, crystal engineering and, the focus of this work, medicinal chemistry. Halogen bonds are important non-covalent interactions playing a role in the recognition of small ligands in halocarbon-protein complexes. Indeed, some proteins are known to have a remarkable propensity to form HaBs, for example, the family of cyclin-dependent kinases, cathepsin L, and the Y220C mutant of the tumor suppressor p53. Thus, the development of computational tools capable of properly describe halocarbon-protein interactions is of utmost importance in the process of rational drug design. The main objective of this Thesis was to develop a new approach, based on molecular docking, that allows the identification of amino acids that can easily be targeted by this interaction, termed halogenbonding hotspots. For that purpose, a large set of compounds containing a moiety capable of halogen bonding (Ph–X, X = Cl, Br, I) were retrieved from the ChEMBL database and docked into the target proteins using AutoDock VinaXB whose scoring function takes into account halogen bonding. Multiple X-ray structures from the protein targets were used to account for conformational variability. Alternatively, if there are few or no X-ray structures available, a standard MD simulation protocol can be employed to generate conformations. Then, the lowest energy pose of each compound is picked and using a geometrical criteria, all halogen atoms engaged in HaBs are selected, thus allowing the identification of HaB hotspots in the binding pocket. Additionally, this method can potentialy identify halogen bonding lead compounds, which is done by checking which compounds consistently scored the best in the several structures of the target proteins while featuring an halogen bond. Our method was validated using two systems, human cathepsin L (hCatL) and the Y220C mutant of the tumor suppressor protein p53 (p53-Y220C). These proteins were chosen since they are well known targets, with amino acids prone to establish HaBs (hCatL: GLY-61 and p53-Y220C: LEU-145). In addition, it allowed us to compare the performance of our method with a recent study that used both of these proteins and co-solvent MD simulations with halobenzene probes to locate HaB hotspots. Our method was able to identify the target residues GLY-61 and LEU-145, in hCatL and p53-Y220C respectively. Moreover, we applied our method in acetylcholinesterase (AChE), since there are virtually no reports in the literature on the use of HaBs to improve its ligand-protein binding affinity. AChE is a commonly addressed therapeutic target for the symptomatic treatment of Alzheimer’s disease (AD). Three important HaB hotspots were identified, which are located near important sites for AChE activity: the peripheral anionic site (SER-293), the acyl site (TYR-124), and the catalytic triad/oxyanion hole (TYR-133, GLU- 202 and HIS-447). AutoDock VinaXB’s ability to predict the experimental poses of hCatL and p53-Y220C mutant proteinligand complexes was assessed. Given the encouraging results, we tested our method to find halogen bonding lead compounds in AChE which explore the identified hotspots. It identified compounds CHEMBL20674 (A) and CHEMBL74515 (B) as leads. Remarkably, lead A has a structure and binding mode identical to donepezil, a drug used in the symptomatic treatment of AD, but establishing an additional halogen bond with the target (GLU-202). On the other hand, lead B has some structural features that resemble galantamine, also a AChE inhibitor used in the symptomatic treatment of AD. Additionally, lead B possess a benzodiazepine moiety, known for being able to cross the blood brain barrier (BBB). These promising results motivated us to attempt the optimization of both lead compounds. From several possible candidates, two were highlighted for each lead. Regarding lead A, the two candidates have similar binding energies to the lead and should be permeable to the blood–brain barrier (BBB) according to a SwissADME prediction. Both feature hydroxyl groups that allow for an extra interaction (hydrogen bond) with the target. Concerning lead B, the two candidates show a slight decrease in binding energies relative to the lead, although SwissADME predicts that these compounds should be BBB-permeable. However, these candidates no longer possess the benzodiazepine moiety which could be an advantage since several studies have shown common side effects of benzodiazepines, such as physical dependence and an increase in risk of developing dementia. In sum, the method developed by our group proved not only capable of identifying halogen bonding hotspots in protein binding sites but also of providing promising lead compounds featuring halogen bonds.Costa, Paulo Jorge Ferreira de Matos, 1980-Repositório da Universidade de LisboaHenriques, Bernardo Miguel Vagarinho2022-12-27T01:31:13Z202020202020-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10451/47979TID:202696235enginfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T16:51:10Zoai:repositorio.ul.pt:10451/47979Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:59:55.644221Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Targeting proteins with halogenated drugs: new strategies to probe halogen-bonding hotspots
title Targeting proteins with halogenated drugs: new strategies to probe halogen-bonding hotspots
spellingShingle Targeting proteins with halogenated drugs: new strategies to probe halogen-bonding hotspots
Henriques, Bernardo Miguel Vagarinho
ligação de halogéneo
s-hole
hotspots de ligação de halogéneo
AutoDock VinaXB
docking molecular
Teses de mestrado - 2020
Departamento de Química e Bioquímica
title_short Targeting proteins with halogenated drugs: new strategies to probe halogen-bonding hotspots
title_full Targeting proteins with halogenated drugs: new strategies to probe halogen-bonding hotspots
title_fullStr Targeting proteins with halogenated drugs: new strategies to probe halogen-bonding hotspots
title_full_unstemmed Targeting proteins with halogenated drugs: new strategies to probe halogen-bonding hotspots
title_sort Targeting proteins with halogenated drugs: new strategies to probe halogen-bonding hotspots
author Henriques, Bernardo Miguel Vagarinho
author_facet Henriques, Bernardo Miguel Vagarinho
author_role author
dc.contributor.none.fl_str_mv Costa, Paulo Jorge Ferreira de Matos, 1980-
Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Henriques, Bernardo Miguel Vagarinho
dc.subject.por.fl_str_mv ligação de halogéneo
s-hole
hotspots de ligação de halogéneo
AutoDock VinaXB
docking molecular
Teses de mestrado - 2020
Departamento de Química e Bioquímica
topic ligação de halogéneo
s-hole
hotspots de ligação de halogéneo
AutoDock VinaXB
docking molecular
Teses de mestrado - 2020
Departamento de Química e Bioquímica
description Tese de mestrado, Química (Química) Universidade de Lisboa, Faculdade de Ciências, 2020
publishDate 2020
dc.date.none.fl_str_mv 2020
2020
2020-01-01T00:00:00Z
2022-12-27T01:31:13Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/masterThesis
format masterThesis
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10451/47979
TID:202696235
url http://hdl.handle.net/10451/47979
identifier_str_mv TID:202696235
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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