Predicting Dyspnea Inducers by Molecular Topology

Gálvez

et al. 2014

J. Chem. Inf. Model.

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We report the discovery of 1-benzyl-2-(3-fluorophenyl)-4-hydroxy-3-(3-phenylpropanoyl)-2H-pyrrole-5-one as a novel non-ligand binding pocket (non-LBP) antagonist of the androgen receptor (AR) through the application of molecular topology techniques. This compound, validated through time-resolved fluorescence resonance energy transfer and fluorescence polarization biological assays, provides the basis for lead optimization and structure-activity relationship analysis of a new series of non-LBP AR antagonists. Induced-fit docking and molecular dynamics studies have been performed to establish a consistent hypothesis for the interaction of the new active molecule on the AR surface.

Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Molecular Topology Applied to the Discovery of 1-Benzyl-2-(3-fluorophenyl)-4-hydroxy-3-(3-phenylpropanoyl)-2H-pyrrole-5-one as a Non-Ligand-Binding-Pocket Antiandrogen

Caboni

Gálvez

et al. 2014

J. Chem. Inf. Model.

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“…In a joint work with L.B. Kier, topochemical descriptors were used for modeling two drug side effects: anorexia [96] and dyspnea [97]. In both cases, despite the complex nature of the property under study, the models were able to predict correctly around 80% of the compounds.…”

Section: New Trends In Qsar: Novel Topological Descriptorsmentioning

confidence: 99%

Latest advances in molecular topology applications for drug discovery

Zanni

Expert Opinion on Drug Discovery

García-Domènech

et al. 2015

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Recent years have witnessed a remarkable rise in QSAR methods based on MT and its application to drug design. New methodologies have been introduced in the area such as QSAR multi-target, Markov networks or perturbation methods. Moreover, novel topological indices, such as Bourgas' descriptors and other new concepts as the derivative of a graph or cliques capable to distinguish between conformers, have also been introduced. New drugs have also been discovered, including anticonvulsants, anineoplastics, antimalarials or antiallergics, just to name a few. In the authors' opinion, MT and QSAR have moved from an attractive possibility to representing a foundation stone in the process of drug discovery.

“…Contrary to the rest of the quantitative structure–activity relationship (QSAR) methods, the MT paradigm relies on chemo-mathematical descriptors. The methodology allows a fast and precise prediction of many biological and physicochemical properties. − Defined as a part of mathematical chemistry, MT is related to the assimilation between molecules and graphs, , so that it can depict molecular structures through graph theoretical indices. , Besides, it deals with the connectivity of atoms in molecules and not with geometrical features such as angles, distances, or tridimensional structures, which are common in standard/conventional approaches. , This way, graph theory and surrounding disciplines stand as basic tools for MT development. By this approach, excellent results have been obtained in the design and selection of new drugs for different pharmacological fields − and more recently in crop protection. , …”

Section: Introductionmentioning

confidence: 99%

Rational Design of Chitin Deacetylase Inhibitors for Sustainable Agricultural Use Based on Molecular Topology

Zanni

Martínez-Cruz

et al. 2022

J. Agric. Food Chem.

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Fungicide resistance is a major concern in modern agriculture; therefore, there is a pressing demand to develop new, greener chemicals. Chitin is a major component of the fungal cell wall and a well-known elicitor of plant immunity. To overcome chitin recognition, fungal pathogens developed different strategies, with chitin deacetylase (CDA) activity being the most conserved. This enzyme is responsible for hydrolyzing the N-acetamido group in N-acetylglucosamine units of chitin to convert it to chitosan, a compound that can no longer be recognized by the plant. In previous works, we observed that treatments with CDA inhibitors, such as carboxylic acids, reduced the symptoms of cucurbit powdery mildew and induced rapid activation of chitin-triggered immunity, indicating that CDA could be an interesting target for fungicide development. In this work, we developed an in silico strategy based on QSAR (quantitative structure-activity relationship) and molecular topology (MT) to discover new, specific, and potent CAD inhibitors. Starting with the chemical structures of few carboxylic acids, with and without disease control activity, three predictive equations based on the MT paradigm were developed to identify a group of potential molecules. Their fungicidal activity was experimentally tested, and their specificity as CDA inhibitors was studied for the three best candidates by molecular docking simulations. To our knowledge, this is the first time that MT has been used for the identification of potential CDA inhibitors to be used against resistant powdery mildew strains. In this sense, we consider of special interest the discovery of molecules capable of stimulating the immune system of plants by triggering a defensive response against fungal species that are highly resistant to fungicides such as powdery mildew.