title: Computational modeling tools for the design of potent antimalarial bisbenzamidines: overcoming the antimalarial potential of pentamidine.
abstract: Malaria is nowadays a worldwide and serious problem with a significant social, economic, and human cost, mainly in developing countries. In addition, the emergence and spread of resistance to existing antimalarial therapies deteriorate the global malaria situation, and lead thus to an urgent need toward the design and discovery of new antimalarial drugs. In this work, a QSAR predictive model based on GETAWAY descriptors was developed which is able to explain with, only three variables, more than 77% of the variance in antimalarial potency and displays a good internal predictive ability (of 73.3% and 72.9% from leave-one-out cross-validation and bootstrapping analyses, respectively). The performance of the proposed model was judged against other five methodologies providing evidence of the superiority of GETAWAY descriptors in predicting the antimalarial potency of the bisbenzamidine family. Moreover, a desirability analysis based on the final QSAR model showed that to be a useful way of selecting the predictive variable level necessary to obtain potent bisbenzamidines. From the proposed model it is also possible to infer that elevated high atomic masses/polarizabilities/van der Waals volumes could play a negative/positive/positive role in the molecular interactions responsible for the desired drug conformation, which is required for the optimal binding to the macromolecular target. The results obtained point out that our final QSAR model is statistically significant and robust as well as possessing a high predictive effectiveness. Thus, the model provides a feasible and practical tool for looking for new and potent antimalarial bisbenzamidines.
authors.affiliation: Applied Chemistry Research Centre, Faculty of Chemistry and Pharmacy, Central University of Las Villas, Santa Clara, Cuba.
authors.forename: Maykel
authors.initials: M
authors.lastname: Cruz-Monteagudo
authors.forename: Fernanda
authors.initials: F
authors.lastname: Borges
authors.forename: Maykel
authors.initials: M
authors.lastname: Perez González
authors.forename: M Natália Dias Soeiro
authors.initials: MN
authors.lastname: Cordeiro
mesh_terms: D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D003198:Computer Simulation; D008958:Models, Molecular; D015394:Molecular Structure; D010419:Pentamidine / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D010419:Pentamidine