1. Could we expect new praziquantel derivatives? A meta pharmacometrics/pharmacoinformatics analysis of all antischistosomal praziquantel derivatives found in the literature
- Author
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Antoine Fortuné, V.B. Ribeiro da Silva, J. El-Methni, A.L. da Silva, Aline Thomas, Brice Hoffmann, Benjamin Boucherle, M. Do Carmo Alves de Lima, Département de pharmacochimie moléculaire (DPM ), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Département de pharmacochimie moléculaire (DPM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Mathématiques Appliquées Paris 5 (MAP5 - UMR 8145), Institut National des Sciences Mathématiques et de leurs Interactions (INSMI)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Unité de recherche en génomique végétale (URGV), and Institut National de la Recherche Agronomique (INRA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Drug ,Chemistry, Pharmaceutical ,First line ,media_common.quotation_subject ,Pharmacoinformatics ,Quantitative Structure-Activity Relationship ,Bioengineering ,Schistosomiasis ,Pharmacology ,Ligands ,01 natural sciences ,Schistosomicides ,parasitic diseases ,Drug Discovery ,Animals ,Humans ,Medicine ,[SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology ,pharmacometrics ,ComputingMilieux_MISCELLANEOUS ,media_common ,Schistosoma ,biology ,010405 organic chemistry ,business.industry ,praziquantel ,fungi ,Low activity ,General Medicine ,[SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences ,biology.organism_classification ,medicine.disease ,Pharmacometrics ,3. Good health ,0104 chemical sciences ,Praziquantel ,meta-analysis ,010404 medicinal & biomolecular chemistry ,Logistic Models ,pharmacoinformatics ,Molecular Medicine ,business ,medicine.drug - Abstract
International audience; Praziquantel (PZQ) is the first line drug for the treatment of human Schistosoma spp. worm infections. However, it suffers from low activity towards immature stages of the worm, and its prolonged use induces resistance/tolerance. During the last 40 years, 263 PZQ analogues have been synthesized and tested against Schistosoma spp. worms, but less than 10% of them showed significant activity. Here, we propose a rationalization of the chemical space of the PZQ derivatives by a ligand-based approach. First, we constructed an in-house database with all PZQ derivatives available in the literature. This analysis shows a high heterogeneity in the data. Fortunately, all studies include PZQ as a reference, permitting the classification of compounds into three classes according to their activities. Models involving ligand-based pharmacophore and logistic regression were performed. Five physicochemical parameters were identified as the best to explain the biological activity. In the end, we proposed new PZQ derivatives with modifications at positions 1 and 7, we analysed them with our models, and we observed that they can be more active than the previously synthesized derivatives. The main goal of this work was to conduct the most valuable meta-pharmacometrics/pharmacoinformatics analysis with all Praziquantel medicinal chemistry data available in the literature.
- Published
- 2019
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