Abstract
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.
Highlights
Schistosomiasis is a neglected disease caused by the parasitic trematode Schistosoma
It is possible to observe four isomeric forms between the EPI, EPIIS, ISOP, and PILO alkaloids (C16H18N2O3), and the presence of optical isomerism between the EPIIS, ISOP, and PILO alkaloids, which is expressly observed in the rotation of the C4 and C9 atoms, and in the chiral carbons C5, C7, and C8, which corroborate with data previously presented in experimental studies [16]
The lowest values of the IR frequencies were identified in PILO, which corroborated the results presented in Fig 2 that demonstrated a lower stability for this alkaloid (S8 Table)
Summary
Schistosomiasis is a neglected disease caused by the parasitic trematode Schistosoma. The interdisciplinary study of neglected diseases and medicinal chemistry is a new area of research that involves the rational planning, evaluation, and synthesis of new drugs in addition to the interpretation of their mode of action at the molecular level and the determination of biological effects arising from their molecular structures [4]. To complement this area of study, computational quantum chemistry has developed new tools to enable modeling and molecular dynamics studies that simulate biological tests and create new possibilities for drug models, without the need for solvent and reagent wastage [5,6,7,8,9]
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