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QSAR and molecular docking studies of 1,3-dioxoisoindoline-4-aminoquinolines as potent antiplasmodium hybrid compounds.

ABSTRACT: Quantitative structure-activity relationships (QSAR) provides a model that link biological activities of compounds to thier chemical stuctures and molecular docking study reveals the interaction between drug and its target enzyme. These studies were conducted on 1,3-dioxoisoindoline-4-aminoquinolines with the aim of producing a model that could be used to design highly potent antiplasmodium. The compounds were first optimized using Density Functional Theory (DFT) with basis set B3LYP/6-31G? then their descriptors calculated. Genetic Function Algorithm (GFA) was used to select descriptors and build the model. One of the four models generated was found to be the best having internal and external squared correlation coefficient (R 2) of 0.9459 and 0.7015 respectively, adjusted squared correlation coefficient (R adj) of 0.9278, leave-one-out (LOO) cross-validation coefficient (Q 2 cv) of 0.8882. The model shows that antiplasmodial activities of 1,3-dioxoisoindoline-4-aminoquinolines depend on ATSC5i, GATS8p, minHBint3, minHBint5, MLFER_A and topoShape descriptors. The model was validated to be predictive, robust and reliable. Hence, it can predict the antiplasmodium activities of new 1,3-dioxoisoindoline-4-aminoquinolines.The docking result indicates strong binding between 1,3-dioxoisoindoline-4-aminoquinolines and Plasmodium falciparum lactate dehydrogenase (pfLDH), and revealed the important of the morpholinyl substituent and amide linker in inhibiting pfLDH. These results could serve as a model for designing novel 1,3-dioxoisoindoline-4-aminoquinolines as inhibitors of PfLDH with higher antiplasmodial activities.

SUBMITTER: Mahmud AW

PROVIDER: S-EPMC7056653 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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QSAR and molecular docking studies of 1,3-dioxoisoindoline-4-aminoquinolines as potent antiplasmodium hybrid compounds.

Mahmud Aliyu Wappah AW Shallangwa Gideon Adamu GA Uzairu Adamu A

Heliyon 20200302 3

Quantitative structure-activity relationships (QSAR) provides a model that link biological activities of compounds to thier chemical stuctures and molecular docking study reveals the interaction between drug and its target enzyme. These studies were conducted on 1,3-dioxoisoindoline-4-aminoquinolines with the aim of producing a model that could be used to design highly potent antiplasmodium. The compounds were first optimized using Density Functional Theory (DFT) with basis set B3LYP/6-31G∗ then ...[more]

PMID: 32154412

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Project description:ObjectiveThis work was designed to study 2,4-disubstituted 6-fluoroquinolines as antiplasmodial agents by using in silico techniques, to aid in the design of novel analogs with high potency against malaria and high inhibition of Plasmodium falciparum translation elongation factor 2 (PfeEF2), a novel drug target.MethodsQuantitative structure-activity relationships (QSAR) of 2,4-disubstituted 6-fluoroquinolines were studied with the genetic function approximation technique in Material Studio software. The 3D structure of PfeEF2 was modeled in the SWISS-MODEL workspace through homology modeling. A molecular docking study of the modeled PfeEF2 and 2,4-disubstituted 6-fluoroquinolines was conducted with Autodock Vina in Pyrx software. Furthermore, the in silico pharmacokinetic properties of selected compounds were investigated.ResultsA robust, reliable and predictive QSAR model was developed that related the chemical structures of 2,4-disubstituted 6-fluoroquinolines to their antiplasmodium activities. The model had an internal squared correlation coefficient R2 of 0.921, adjusted squared correlation coefficient R2adj of 0.878, leave-one-out cross-validation coefficient Q2cv of 0.801 and predictive squared correlation coefficient R2pred of 0.901. The antiplasmodium activity of 6-fluoroquinolines was found to depend on the n5Ring, GGI9, TDB7u, TDB8u and RDF75i physicochemical properties: n5Ring, TDB8u and RDF75i were positively associated, whereas GGI9 and TDB7u were negatively associated, with the antiplasmodium activity of the compounds. Stable complexes formed between the compounds and modeled PfeEF2, with binding affinity ranging from -8.200 to -10.700 kcal/mol. Compounds 5, 11, 16, 22 and 24 had better binding affinities than quinoline-4-carboxamide (DDD107498), as well as good pharmacokinetic properties, and therefore may be better inhibitors of this novel target.ConclusionQSAR and docking studies provided insight into designing novel 2,4-disubstituted 6-fluoroquinolines with high antiplasmodial activity and good structural properties for inhibiting a novel antimalarial drug target.

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QSAR and molecular docking studies of 1,3-dioxoisoindoline-4-aminoquinolines as potent antiplasmodium hybrid compounds.

Publications

QSAR and molecular docking studies of 1,3-dioxoisoindoline-4-aminoquinolines as potent antiplasmodium hybrid compounds.

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