IBC'2023
Our Speakers
International Bioinformatics Conference IBC’2023
01.
Antonio Viayna Gaza, PhD
Department of Nutrition, Food Science and Gastronomy, Faculty of Pharmacy and Food Sciences, Institute of Biomedicine (IBUB), and Institute of Theoretical and Computational Chemistry (IQTC-UB), University of Barcelona, Santa Coloma de Gramanet E-08921, Spain
Title: ”Targeting PfGluPho as a Promising Strategy for Developing Selective Antimalarial Drugs”
Glucose-6-phosphate dehydrogenase-6-phosphogluconolactonase (PfGluPho) plays a pivotal role in the Pentose Phosphate Pathway (PPP) of Plasmodium falciparum, a crucial factor for its development inside the human body, as it serves as a major source of NADPH. Given the structural disparities between PfGluPho and its human homolog, it presents a promising role as a potential target for the development of selective antimalarial drugs against Malaria. Our research motivations have been focused on exploring various compounds described in literature that exhibit selective inhibitory effects on PfGluPho. Understanding the binding mode of these compounds is essential for identifying the molecular determinants responsible for their activity and paving the way for the design of novel antimalarial agents. Another key challenge in our research lies in the absence of an X-ray 3D structure of the Plasmodium falciparum enzyme form. To overcome this limitation, we have employed a combination of homology modeling techniques, molecular docking, and molecular dynamics simulations to generate a reliable 3D model. This 3D structure will potentially serve as a facilitator to design new and effective PfGluPho selective inhibitors. In present conference, we will summarize the diverse strategies and significant progress made by our research group in both the identification of potential inhibitors for PfGluPho and the elucidation of its 3D structure. These findings hold promise for the development of innovative and targeted antimalarial therapies, bringing us closer to combatting Malaria effectively. Read more
02.
Prof. Younes Smani
Andalusian Center of Developmental Biology, Pablo de Olavide University, Seville, Spain
Title:ﾠ“Title: Innovative antimicrobial strategy for the treatment of MDR bacterial infection”
The development of new approaches that adjuvant the scarcity of clinically relevant antibiotics for treatment of infections by multidrug-resistant Gram negative bacteria is an urgent need. Previously, we showed that tamoxifen, an anti-cancer drug, presents very promising therapeutic efficacy in animal models of infection with MDR Gram negative bacteria such asﾠAcinetobacter baumannii,ﾠPseudomonas aeruginosaﾠandﾠEscherichia coliﾠby modulating the migration of immune cells from bone marrow to blood and reducing the hyperinflammation [Mir-Canturri A, et al. Pharmaceuticals 2021], and metabolizing tamoxifen to three major metabolites (desmethyltamoxifen, hydroxytamoxifen and endoxifen) that exhibit high antibacterial activity against thisﾠA. baumanniiﾠandﾠE. coliﾠin vitroﾠ[Mir-Canturri A, et al. Antibiotics 2021]. However, the molecular target(s) of the tamoxifen metabolites (MET), remain to be determined.
Using a transposon library of a collection of 9504 random transposon mutants ofﾠA. baumanniiﾠATCC 17978 strain, we select two mutants resistant to MET. To further determine whether MET affects their membrane structure, permeability and OMPs profile, we perform analysis byﾠtransmission electron microscopy, fluorescence assays, SDS-PAGE and qRT-PCR, respectively. We show thatﾠboth mutant strains treated with MET presented lower membrane permeabilization and suffered morphological changes and reduction in OmpW expression. In order to confirm that OmpW is the target of MET, molecular docking of these metabolites against OmpW was performed. We find that MET binding to OmpW presented higher score. This data has been confirmed by the MET susceptibility profile of the mutant ofﾠA. baumanniiﾠdeficient in OmpW which has presented MIC value 8-folds higher than the isogenic wt strain. In addition, we performﾠchequerboard and time-kill curve analysesﾠto determine whether MET can synergize with clinically used antibiotic such as colistin. We find that MET is more synergistic with colistin against colistin-resistantﾠA, baumanniiﾠduring.ﾠFinally, and using mice, we determine the toxicity and pharmacokinetic parameters of MET.
Overall, our data showed that ompW might be involved in the mechanism of action of MET againstﾠA. baumannii, and advanced our knowledge on the antimicrobial activity of MET as new therapeutic indication.
03.
Prof. Abdurrahman Olğaç
Gazi University, Ankara 06560, Turkey
Title: “A Tale of Two 5-Lipoxygenase Activating Protein (FLAP) Inhibitors“
FLAP is responsible for regulating leukotriene (LT) biosynthesis. It is an integral membrane protein and acts as an anchor to activate 5-lipoxygenase (5-LO) and transfer arachidonic acid (AA) to 5-LO. Through this activation, AA is metabolized, and LT metabolites are produced. Inhibition of LT biosynthesis is a promising strategy for treating various types of inflammatory diseases. In this work, we will present the development story of quinazoline-4(3H)-one-7-carboxamides and 1,2,4-triazoles as FLAP antagonists which were discovered through a virtual screening (VS) study (IC50 values were identified as 0.87 and 2.18 μM) [1]. By further development studies, quinazolinone derivatives were designed to dually inhibit FLAP and soluble epoxide hydrolase (sEH) [2] and triazole derivatives were designed to block 5-LO product formation through binding to FLAP [3]. The structural modifications on the most potent quinazolinone derivative reached 0.70 μM for sEH and 2.70 μM for FLAP, and the most potent triazole derivative reached 1.15 μM for FLAP. These structures can become a more potent FLAP-antagonist via further developments by following the hints derived from structure-activity relationship data and computational analysis.
References:
[1] Olgac, A., et al., Discovery of Novel 5-Lipoxygenase-Activating Protein (FLAP) Inhibitors by Exploiting a Multistep Virtual Screening Protocol. Journal of Chemical Information and Modeling, 2020. 60(3): p. 1737-1748.
[2] Turanli, S., et al., Quinazoline-4(3H)-one-7-carboxamide Derivatives as Human Soluble Epoxide Hydrolase Inhibitors with Developable 5-Lipoxygenase Activating Protein Inhibition. ACS Omega, 2022. 8(41): p. 36354-36365.
[3] Olgac, A., Capan I., Dahlke P., et al., Substituted 1,2,4-triazoles as novel and selective inhibitors of leukotriene biosynthesis targeting 5-lipoxygenase-activating protein (FLAP). ACS Omega, 2023. (Just accepted)
04.
Carolina Estarellas Martín, PhD
Department of Nutrition, Food Science and Gastronomy, Faculty of Pharmacy and Food Sciences, Institute of Theoretical and Computational Chemistry (IQTC-UB), University of Barcelona, Santa Coloma de Gramanet E- 08921, Spain
Title: “Revealing the different structure-dynamic relationship of CutC between microorganisms: from protein dynamics to drug design“
Cardiovascular diseases (CVDs) are the leading cause of death globally, taking an estimated 17.9 million lives each year, with one third of these deaths occurring prematurely in people under 70 years of age. Some chronic metabolic diseases, like obesity and diabetes, contribute significantly to the development of CVDs, which have a severe socieconomical impact on the public health worldwide, making the development of more effective treatments an urgent challenge.
Our aim is to explore the development of new therapeutic strategy for tackling CVDs from a new perspective, since it is focused on a relevant and novel target implicated in the regulation of vascular function: the choline trimethylamine(TMA)-lyase, CutC. CutC belongs to the Glycyl Radical Enzyme (GRE) family, being the first enzyme of this family able to cleave a C-N bond.1–3 Its recent discovery has opened a new avenue for the treatment of CVDs through microbiota-targeted drug discovery pipelines, since it is solely found in the human gut microbiota (GM). The choline derivatives can be metabolized to trimethylamine (TMA) through CutC/CutD pair. Since there are no pathways in human cells capable of synthesizing TMA, the gut microbiota represents the only source of this metabolite. Once formed, TMA can be absorbed in the intestines and delivered to the liver, where it is oxidized to TMAO, which is linked to diseases such as atherosclerosis, Type II Diabetes Mellitus and heart and liver failure.
We have performed molecular dynamics (MD) simulations of CutC in its monomeric state from D. alaskensis and K. pneumoniae microorganisms, both from proteobacteria phyla. Our results reveal the occurrence of different conformational behavior between apo and holo states and, very interestingly between microorganisms. While the results of D. alaskensis indicate a movement that connect the glycyl radical enzyme through the active site, suggesting a potential implication in the CutC dimer complex; the simulations of K. pneumoniae required to build up a homology modeling, which was performed with I- Tasser and Swiss- Model. Surprisingly, both webservers renders different initial 3D structures for the apo state (PDB code:5A0Z), and MD simulations where run for both. The results indicate different conformational behavior, in two flexible regions near to the active site and a priori not directly involved with the glycyl radical domain. The dynamics observed in this region shed some light in the area where CutD could be approached to CutC to transfer the radical for the reaction mechanism. Altogether, these results open novel opportunities to explore for the design of CutC inhibitors.
References:
[1] Bodea, S., et al. Cell Chemical Biology 2016, 23, 10.
[2] Craciun, S., Balskus, E. P. Proc Natl Acad Sci U S A 2012, 109, 52.
[3] Kalnins, G., et al. J of Biological Chemistry 2015, 290, 35.
[4] Balskus E. P., et al. J Am Chem Soc 2019, 141, 1.
05.
Prof. Samir Chtita
Laboratoire de chimie analytique et moléculaire,
Faculté des sciences Ben M’Sik, Université Hassan II de Casablanca, Maroc.
Title: “Applications des méthodes de la modélisation moléculaire dans la conception des molécules d’intérêt thérapeutique“
L’utilisation de méthodes et d’outils chémoinformatiques dans l’analyse et la comparaison de chimiothèques a montré son intérêt et son efficacité récemment. En effet, avec l’émergence de la pandémie de la COVID-19 le recours à ces méthodes est devenu incontournable. Ces méthodes constituent également une interface entre différentes champs disciplinaire regroupant la chimie, la biologie et l’informatique. Elle permet, grâce aux programmes informatiques, de rassembler des données d’analyses physicochimiques, biologiques et structurales dans une unité de lieu et de temps. Les modèles moléculaires qui en découlent font la synthèse des informations de ces différentes sources et participent ainsi à la compréhension des mécanismes d’interaction entre les petites molécules bioactives et leur cible biologique. La modélisation moléculaire fournit également des outils efficaces d’aide à la conception et à la sélection de nouvelles structures par la simulation de leurs interactions et par des prévisions quantitatives d’activité biologique.
Dans cette conférence, nous allons donner un aperçu général sur des techniques employées dans la conception in silico des candidats de médicaments. Puis, nous allons présenter la stratégie employée pour l’utilisation des méthodes de modélisation moléculaire, notamment les méthodes QSAR, le docking moléculaire et la dynamique moléculaire. Et enfin, nous allons présenter et discuter quelques résultats obtenus lors de l’utilisation de ces méthodes dans l’évaluation et la proposition de nouveaux composés bioactifs d’origine naturelle et synthétique susceptible de manifester une activité prometteuse contre certaines maladies émergentes.
