Browsing by Author "Bustos, Daniel"

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    Chalcone derivatives as non-canonical ligands of TRPV1
    (2019) Benso, Bruna; Bustos, Daniel; Zarraga, Miguel O.; González, Wendy; Caballero, Julio; Brauchi, Sebastián
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    Cost-Effective Pipeline for a Rational Design and Selection of Capsaicin Analogues Targeting TRPV1 Channels
    (2023) Bustos, Daniel; Galarza, Christian; Ordonez, Wilson; Brauchi, Sebastian; Benso, Bruna
    Transient receptor potential (TRP) channels constitute a large group of membrane receptors associated with sensory pathways in vertebrates. One of the most studied is TRPV1, a polymodal receptor tuned for detecting heat and pungent compounds. Specific inhibition of the nociceptive transduction at the peripheral nerve represents a convenient approach to pain relief. While acting as a chemoreceptor, TRPV1 shows high sensitivity and selectivity for capsaicin. In contrast to the drugs available on the market that target the inflammatory system, TRPV1 antagonists act as negative modulators of nociceptive transduction. Therefore, the development of com-pounds modulating TRPV1 activity has expanded dramatically over time. Experimental data suggest that most agonist and antagonist drugs interact at or near capsaicin's binding site. In particular, the properties of capsaicin's head play an essential role in modulating potency and affinity. Here, we explored a cost-efficient pipeline to predict the effects of introducing chemical modifications into capsaicin's head region. An extensive set of molecules was selected by first considering the geometrical properties of capsaicin's binding site and then molecular docking. Finally, the novel ligands were ranked by combining molecular and pharmacokinetic predictions.
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    Nature of host-guest interaction of cyclic alcohols in β-Cyclodextrin: A molecular view of its structural features
    (2025) Cantero-Lopez, Plinio; Sanchez, Julio; Meza, Manuel S. Paez; Garcia-Negrete, C. A.; Bustos, Daniel; Yanez, Osvaldo
    Host- guest complexes are commonly found in several disciplines such as biochemistry, cosmetics, food, pharmaceuticals, and the environment. Studying the relationships between host and guest is essential in this context to understand their physicochemical behavior. This study aimed to examine the intermolecular interactions of cyclic alcohols within n- cyclodextrin (n- CD). The experimental spectroscopic results demonstrated the formation of the studied complexes. In this work, two orientations were used: orientation A (hydroxyl group toward the primary hydroxyl of n- CD) and orientation B (hydroxyl group toward the secondary hydroxyl of n- CD). The results indicate that regardless of the orientation used, the profile energy is thermodynamically favorable. However, there are differences in terms of greater or less stability in terms of the thermodynamic parameters studied. Physicochemical properties demonstrate that the host-guest complex forms spontaneously, and exothermic mode. The interaction between cyclic alcohols and n- CD in orientation A promotes a more pronounced deformation of the secondary edge of n- CD. Moreover, the arrangement of molecules demonstrates that intramolecular hydrogen bonds are less stable between the glycosidic units of n- CD. This arrangement may help or hinder the development of intermolecular hydrogen bonds.
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    Novel apocynin regulates TRPV1 activity in the trigeminal system and controls pain in a temporomandibular joint neurogenic model
    (2024) Machado, Taisa Maria Mendes Matuiama; Aquino, Iara Goncalves; Franchin, Marcelo; Zarraga, Miguel O.; Bustos, Daniel; Spada, Fernanda Papa; Napimoga, Marcelo Henrique; Clemente-Napimoga, Juliana Trindade; Alencar, Severino Matias; Benso, Bruna; Abdalla, Henrique Ballassini
    Objective: Herein, we investigate the potential analgesic effect of a newly synthesized chalcone-derived apocynin in a neurogenic pain model. Methods: Molecular docking was used to foretell the apocynin binding features and dynamics with the TRPV1 channel, and the activity was tested in vitro, using transfected HEK 293T cells with the rat TRPV1 receptor. The analgesic effect of apocynin was investigated using a capsaicin-induced pain model. The expression of TRPV1, TRPA1, TRPM8, and MAPKs was assessed by electrophoresis, and immunosorbent assays were performed to quantify the neurotransmitters Substance P, Glutamate, and CGRP. A survival assay using Galleria mellonella was carried out to determine the toxicity. Results: We observed that apocynin exhibits greater thermodynamic stability. Upon apocynin ligand binding, it changes the electrostatic potential for a predominantly electronegative state in the interior and neutral in its external vanilloid pocket. Treatment of apocynin induces antinociceptive effects against the noxious challenge of capsaicin. Histologically, apocynin decreased the number of TRPV1+ immunopositive cells. Electrophoresis showed reduced phosphorylation of p44/42 (ERK1/2) and decreased protein levels of substance P, and CGRP. In the survival assay, apocynin showed low toxicity. Conclusions: In conclusion, we provide proof-of-principles that the newly synthesized apocynin compound effectively prevented nociception in a neurogenic model of orofacial pain.
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    Unveiling Novel Urease Inhibitors for Helicobacter pylori: A Multi-Methodological Approach from Virtual Screening and ADME to Molecular Dynamics Simulations
    (2024) Valenzuela-Hormazabal, Paulina; Sepulveda, Romina V.; Alegria-Arcos, Melissa; Valdes-Munoz, Elizabeth; Rojas-Perez, Victor; Gonzalez-Bonet, Ileana; Suardiaz, Reynier; Galarza, Christian; Morales, Natalia; Leddermann, Veronica; Castro, Ricardo I.; Benso, Bruna; Urra, Gabriela; Hernandez-Rodriguez, Erix W.; Bustos, Daniel
    Helicobacter pylori (Hp) infections pose a global health challenge demanding innovative therapeutic strategies by which to eradicate them. Urease, a key Hp virulence factor hydrolyzes urea, facilitating bacterial survival in the acidic gastric environment. In this study, a multi-methodological approach combining pharmacophore- and structure-based virtual screening, molecular dynamics simulations, and MM-GBSA calculations was employed to identify novel inhibitors for Hp urease (HpU). A refined dataset of 8,271,505 small molecules from the ZINC15 database underwent pharmacokinetic and physicochemical filtering, resulting in 16% of compounds for pharmacophore-based virtual screening. Molecular docking simulations were performed in successive stages, utilizing HTVS, SP, and XP algorithms. Subsequent energetic re-scoring with MM-GBSA identified promising candidates interacting with distinct urease variants. Lys219, a residue critical for urea catalysis at the urease binding site, can manifest in two forms, neutral (LYN) or carbamylated (KCX). Notably, the evaluated molecules demonstrated different interaction and energetic patterns in both protein variants. Further evaluation through ADMET predictions highlighted compounds with favorable pharmacological profiles, leading to the identification of 15 candidates. Molecular dynamics simulations revealed comparable structural stability to the control DJM, with candidates 5, 8 and 12 (CA5, CA8, and CA12, respectively) exhibiting the lowest binding free energies. These inhibitors suggest a chelating capacity that is crucial for urease inhibition. The analysis underscores the potential of CA5, CA8, and CA12 as novel HpU inhibitors. Finally, we compare our candidates with the chemical space of urease inhibitors finding physicochemical similarities with potent agents such as thiourea.