[PMC free article] [PubMed] [Google Scholar] 3

[PMC free article] [PubMed] [Google Scholar] 3. could predict the correct molecular target of market drugs, such as artemisinin. In addition, our findings suggested a new pharmacological mechanism for quinine, which includes inhibition of falcipain-II and a potential new antimalarial candidate, clioquinol. MAIN CONCLUSIONS The BraMMT is available to perform vHTS experiments using OCTOPUS or software to improve 4-O-Caffeoylquinic acid the search for new antimalarial compounds. It can be retrieved from www.drugdiscovery.com.br or download of Supplementary data. molecular 4-O-Caffeoylquinic acid targets retrieved from the PDB. This data bank permits vHTS experiments against a pool of molecular targets. In this paper, the BraMMT was evaluated through docking tools and a set of known antimalarial compounds. MATERIALS AND METHODS – The three-dimensional structures of the receptors were obtained from the PDB database from their respective codes 14 using the key word: ATPase calcium pump ortholog (PfATP6) and hexose transporter (PfHT) were constructed by comparative modeling. 15 , 16 Thereafter, the molecular targets were prepared by removing the replicate residue present at the binding site. Moreover, only water molecules that carried out at least two interactions between the ligand and molecular target were kept. 7 , 10 Further, the protonation state of each target was adjusted according to the pH of the enzymatic environment using the PROPKA module (academic version) of the Maestro software. Finally, the druggability of each target was evaluated by TDR platform targets (http://tdrtargets.org). This characteristic predicts whether a protein can bind with high affinity and specificity to small compounds. – Re-docking methodology was carried out to evaluate the AutoDock Vina program. 11 , 17 All calculations were made in triplicate and expressed as the mean. For each target, the AutoDock Tools program was used to obtain the 20 ? boxes and the x, y, and z coordinates, with spaced points of 1 1 ? centered on the ligand. In addition, the crystallographic structures without ligand, a search for equivalent structure belongs to another organism, was performed using the BLAST program. The degree of identity was greater than 27%, which is considered satisfactory to use the active compounds belonging to the target in another organism. 18 Hence, the atomic molecular coordinates of the ligand were transferred from the structure found by BLAST to the structure following a re-docking process. The crystallographic and re-docking ligands were overlaid for calculation of root mean square deviation (RMSD) using the Discovery Visualizer 4.5 program. Additionally, the receiver-operator characteristic (ROC curve) and the area under the ROC curve (AUC) were established for each molecular target to evaluate Mouse monoclonal to ABCG2 the ability of the molecular docking methodology to differentiate the active molecules from decoys (false positives). 19 For each molecular target from BraMMT, at least two active compounds with the lowest Ki or IC50 value were selected from ChEMBL. 20 Subsequently, inactive compounds (decoys) were obtained from the active compounds for each molecular target using the DUD-E platform. Decoys had similar physical properties, such as molecular mass, number of rotational bonds, Log P, and number of hydrogen bond donor/hydrogen bond acceptor groups. Following, the curves, ROC and AUC, were built using SPSS Statistics for Windows software. Active compounds and decoys were submitted to the molecular docking calculations in the AutoDock Vina program 11 , 17 using OCTOPUS, 12 in which the configuration files were determined through a re-docking step. – The BraMMT data bank was evaluated using 27 antimalarial drugs [see Supplementary data (Table V)] listed by the World Health Organization (WHO) (https://www.ebi.ac.uk/chembl/malaria/drugstor). These molecules were selected from the ChEMBL platform for TBVS through OCTOPUS, 12 maintaining the parameters used in the molecular re-docking step [see Supplementary data (Table I)]. Finally, the 27 antimalarial drugs were ranked using the Equation 1, which ? values were obtained by the difference between the crystallographic ligand binding energy (obtained from the re-docking step) and antimalarial drugs binding energy (obtained from the vHTS process). Thus, the values greater than 4-O-Caffeoylquinic acid 0 demonstrated that.