title: Rational Design of Antimalarial Drugs Using Molecular Modeling and Statistical Analysis.
abstract: Artemisinin is an antimalarial compound isolated from Artemisia annua L. that is effective against Plasmodium falciparum. This paper proposes the development of new antimalarial derivatives of artemisinin from a SAR study and statistical analysis by multiple linear regression (MLR). The HF/6-31G** method was used to determine the molecular properties of artemisinin and 10 derivatives with antimalarial action. MEP maps and molecular docking were used to study the interface between ligand and receptor (heme). The Pearson correlation was used to choose the most important properties interrelated to the antimalarial activity: Hydration Energy (HE), Energy of the Complex (Ecplex), bond length (FeO1), and maximum index of R/Electronegativity of Sanderson (RTe+). After the Pearson correlation, 72 MLR models were built between antimalarial activity and molecular properties; the statistical quality of the models was evaluated by means of correlation coefficient (r), squared correlation coefficient (r(2)), explained variance (adjusted R(2)), standard error of estimate (SEE), and variance ratio (F), and only four models showed predictive ability. The selected models were used to predict the antimalarial activity of ten new artemisinin derivatives (test set) with unknown activity, and only eight of these compounds were predicted to be more potent than artemisinin, and were therefore subjected to theoretical studies of pharmacokinetic and toxicological properties. The test set showed satisfactory results for six new artemisinin compounds which is a promising factor for future synthesis and biological assays.
authors.affiliation: Laboratory of Modeling and Computational Chemistry, Federal University of Amapa, Macapa, Amapa, 68902-280, Brazil. breno@unifap.br.
authors.forename: Cleydson Breno Rodrigues dos
authors.initials: CB
authors.lastname: Santos
authors.forename: Cleison Carvalho
authors.initials: CC
authors.lastname: Lobato
authors.forename: Francinaldo Sarges
authors.initials: FS
authors.lastname: Braga
authors.forename: Josivan da Silva
authors.initials: Jda S
authors.lastname: Costa
authors.forename: Hugo Alexandre Silva
authors.initials: HA
authors.lastname: Favacho
authors.forename: Jose Carlos Tavares
authors.initials: JC
authors.lastname: Carvalho
authors.forename: Williams Jorge da Cruz
authors.initials: WJ
authors.lastname: Macedo
authors.forename: Davi Do Socorro Barros
authors.initials: Ddo S
authors.lastname: Brasil
authors.forename: Carlos Henrique Tomich de Paula da
authors.initials: CH
authors.lastname: Silva
authors.forename: Lorane Izabel da
authors.initials: LI
authors.lastname: Silva Hage-Melim
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D037621:Artemisinins / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D018938:Caco-2 Cells; D004285:Dogs; D015195:Drug Design; D006801:Humans; D008024:Ligands; D016014:Linear Models; D061985:Madin Darby Canine Kidney Cells; D008958:Models, Molecular; D015233:Models, Statistical; D062105:Molecular Docking Simulation; D010963:Plasmodium falciparum / Q000187:drug effects*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D008024:Ligands; C031327:artemisinin