What place does molecular topology have in today’s drug discovery?

Zanni, Riccardo; Gálvez-Llompart, María; García-Domènech, Ramón; Gálvez, Jorge

doi:10.1080/17460441.2020.1770223

Cited by 22 publications

(15 citation statements)

References 86 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this sense, the EDTA molecule could be an interesting lead chemical for fungicide design. One of the most promising computer-aided drug design methods is molecular topology [45]. Unlike the rest of the quantitative structure-activity relationship (QSAR) methods, the molecular topology paradigm uses only pure mathematical descriptors.…”

Section: Discussionmentioning

confidence: 99%

Chitin Deacetylase, a Novel Target for the Design of Agricultural Fungicides

Martínez-Cruz

Polonio

Zanni

et al. 2021

JoF

Self Cite

View full text Add to dashboard Cite

Fungicide resistance is a serious problem for agriculture. This is particularly apparent in the case of powdery mildew fungi. Therefore, there is an urgent need to develop new agrochemicals. Chitin is a well-known elicitor of plant immunity, and fungal pathogens have evolved strategies to overcome its detection. Among these strategies, chitin deacetylase (CDA) is responsible for modifying immunogenic chitooligomers and hydrolysing the acetamido group in the N-acetylglucosamine units to avoid recognition. In this work, we tested the hypothesis that CDA can be an appropriate target for antifungals using the cucurbit powdery mildew pathogen Podosphaera xanthii. According to our hypothesis, RNAi silencing of PxCDA resulted in a dramatic reduction in fungal growth that was linked to a rapid elicitation of chitin-triggered immunity. Similar results were obtained with treatments with carboxylic acids such as EDTA, a well-known CDA inhibitor. The disease-suppression activity of EDTA was not associated with its chelating activity since other chelating agents did not suppress disease. The binding of EDTA to CDA was confirmed by molecular docking studies. Furthermore, EDTA also suppressed green and grey mould-causing pathogens applied to oranges and strawberries, respectively. Our results conclusively show that CDA is a promising target for control of phytopathogenic fungi and that EDTA could be a starting point for fungicide design.

show abstract

Section: Discussionmentioning

confidence: 99%

Chitin Deacetylase, a Novel Target for the Design of Agricultural Fungicides

Martínez-Cruz

Polonio

Zanni

et al. 2021

JoF

Self Cite

View full text Add to dashboard Cite

show abstract

“…During the last decade, MT showed substantial results in drug design, leading to the identification of several new lead molecules in diverse pharmacological and chemical areas. 19 …”

Section: Resultsmentioning

confidence: 99%

“…During the last decade, MT showed substantial results in drug design, leading to the identification of several new lead molecules in diverse pharmacological and chemical areas. 19 In this work, four QSAR models were developed. The first model focused on the identification of compounds showing JAK inhibitory activity without preferences regarding the subtypes (hereafter referred to as the general model and mathematically described by the discriminant function DF gen ).…”

Section: Resultsmentioning

confidence: 99%

“…MT coupled to LDA allows deriving specific equations (or discriminant functions, DFs) that can be used for predicting if a molecule, not included in the development of the model, will act as an inhibitor or otherwise it will be inactive. During the last decade, MT showed substantial results in drug design, leading to the identification of several new lead molecules in diverse pharmacological and chemical areas …”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Targeting the JAK/STAT Pathway: A Combined Ligand- and Target-Based Approach

Gálvez-Llompart

Ocello

Rullo

et al. 2021

J. Chem. Inf. Model.

Self Cite

View full text Add to dashboard Cite

Janus kinases (JAKs) are a family of proinflammatory enzymes able to mediate the immune responses and the inflammatory cascade by modulating multiple cytokine expressions as well as various growth factors. In the present study, the inhibition of the JAK–signal transducer and activator of transcription (STAT) signaling pathway is explored as a potential strategy for treating autoimmune and inflammatory disorders. A computationally driven approach aimed at identifying novel JAK inhibitors based on molecular topology, docking, and molecular dynamics simulations was carried out. For the best candidates selected, the inhibitory activity against JAK2 was evaluated in vitro . Two hit compounds with a novel chemical scaffold, 4 (IC 50 = 0.81 μM) and 7 (IC 50 = 0.64 μM), showed promising results when compared with the reference drug Tofacitinib (IC 50 = 0.031 μM).

show abstract

“…In this study, we show the potential of a new, multidisciplinary collaboration between two research groups: one group engaged in computer-aided drug design led by Prof. Jorge Galvez [ 17 , 18 , 19 ] and Prof. Subhash Basak [ 20 , 21 , 22 ], and the other led by a virologist Prof. Sagar Goyal [ 23 ] with expertise in pathogenesis and control of viral infections. From the synergy of these groups, a research unit for the development of early strategies effective against future pandemics has been established.…”

Section: Introductionmentioning

confidence: 99%

COVID-19 and the Importance of Being Prepared: A Multidisciplinary Strategy for the Discovery of Antivirals to Combat Pandemics

et al. 2022

Self Cite

View full text Add to dashboard Cite

During an emergency, such as a pandemic in which time and resources are extremely scarce, it is important to find effective and rapid solutions when searching for possible treatments. One possibility in this regard is the repurposing of available “on the market” drugs. This is a proof of the concept study showing the potential of a collaboration between two research groups, engaged in computer-aided drug design and control of viral infections, for the development of early strategies to combat future pandemics. We describe a QSAR (quantitative structure activity relationship) based repurposing study on molecular topology and molecular docking for identifying inhibitors of the main protease (Mpro) of SARS-CoV-2, the causative agent of COVID-19. The aim of this computational strategy was to create an agile, rapid, and efficient way to enable the selection of molecules capable of inhibiting SARS-CoV-2 protease. Molecules selected through in silico method were tested in vitro using human coronavirus 229E as a surrogate for SARS-CoV-2. Three strategies were used to screen the antiviral activity of these molecules against human coronavirus 229E in cell cultures, e.g., pre-treatment, co-treatment, and post-treatment. We found >99% of virus inhibition during pre-treatment and co-treatment and 90–99% inhibition when the molecules were applied post-treatment (after infection with the virus). From all tested compounds, Molport-046-067-769 and Molport-046-568-802 are here reported for the first time as potential anti-SARS-CoV-2 compounds.

show abstract

What place does molecular topology have in today’s drug discovery?

Cited by 22 publications

References 86 publications

Chitin Deacetylase, a Novel Target for the Design of Agricultural Fungicides

Chitin Deacetylase, a Novel Target for the Design of Agricultural Fungicides

Targeting the JAK/STAT Pathway: A Combined Ligand- and Target-Based Approach

COVID-19 and the Importance of Being Prepared: A Multidisciplinary Strategy for the Discovery of Antivirals to Combat Pandemics

Contact Info

Product

Resources

About