Computational quantum chemistry, molecular docking, and ADMET predictions of imidazole alkaloids of Pilocarpus microphyllus with schistosomicidal properties

• Published in: PloS one Vol. 13; no. 6; p. e0198476
• Main Authors: Rocha, Jefferson A, Rego, Nayra C S, Carvalho, Bruna T S, Silva, Francisco I, Sousa, Jose A, Ramos, Ricardo M, Passos, Ionara N G, de Moraes, Josué, Leite, Jose R S A, Lima, Francisco C A
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 26-06-2018; Public Library of Science (PLoS)
• Subjects: 4-Butyrolactone - analogs & derivatives; 4-Butyrolactone - chemistry; 4-Butyrolactone - pharmacology; 5'-Methylthioadenosine phosphorylase; Adenosine; Alkaloids; Alkaloids - chemistry; Alkaloids - pharmacology; Animals; Anthelmintics; Anthelmintics - chemistry; Anthelmintics - pharmacology; Antifungal agents; Arginase; Biology and Life Sciences; Biotechnology; Carcinogens; Chemical properties; Chemistry; Computational chemistry; Computer applications; Disease; Enzymes; Excretion; Glutathione; Glutathione reductase; Health aspects; Histone deacetylase; Imidazole; Imidazoles; Imidazoles - chemistry; Imidazoles - pharmacology; Isomers; Jaborandi; Libraries; Mathematical models; Medicine and Health Sciences; Metabolites; Models, Molecular; Molecular chains; Molecular docking; Molecular Docking Simulation; Molecular properties; Optimization; Organic chemistry; Permeability; Pharmaceutical chemistry; Pharmaceutical sciences; Pharmacodynamics; Pharmacognosy; Pharmacokinetics; Pharmacological research; Pharmacology; Phosphorylase; Physical Sciences; Pilocarpus; Pilocarpus - chemistry; Pilocarpus microphyllus; Plant Extracts - pharmacology; Plant metabolites; Praziquantel; Quantum chemistry; Quantum Theory; R&D; Research & development; Schistosoma; Schistosoma mansoni; Schistosoma mansoni - drug effects; Schistosomiasis; Software; Thermodynamics; Thioredoxin; Toxicity; Uridine; Uridine phosphorylase; Brazil
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0198476

Schistosomiasis affects million people and its control is widely dependent on a single drug, praziquantel. Computational chemistry has led to the development of new tools that predict molecular properties related to pharmacological potential. We conducted a theoretical study of the imizadole alkaloids of Pilocarpus microphyllus (Rutaceae) with schistosomicidal properties. The molecules of epiisopiloturine, epiisopilosine, isopilosine, pilosine, and macaubine were evaluated using theory models (B3lyp/SDD, B3lyp/6-31+G(d,p), B3lyp/6-311++G(d,p)). Absorption, distribution, metabolization, excretion, and toxicity (ADMET) predictions were used to determine the pharmacokinetic and pharmacodynamic properties of the alkaloids. After optimization, the molecules were submitted to molecular docking calculations with the purine nucleoside phosphorylase, thioredoxin glutathione reductase, methylthioadenosine phosphorylase, arginase, uridine phosphorylase, Cathepsin B1 and histone deacetylase 8 enzymes, which are possible targets of Schistosoma mansoni. The results showed that B3lyp/6-311++G(d,p) was the optimal model to describe the properties studied. Thermodynamic analysis showed that epiisopiloturine and epiisopilosine were the most stable isomers; however, the epiisopilosine ligand achieved a superior interaction with the enzymes studied in the molecular docking experiments, which corroborated the results of previous experimental studies on schistosomiasis.