Computational protocol: Synthesis, SAR, and Docking Studies Disclose 2-Arylfuran-1,4-naphthoquinones as In Vitro Antiplasmodial Hits

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Protocol publication

[…] Initially, the molecular targets were obtained from a Protein Data Bank (PDB) [] under codes 4PD4 (P. falciparum cytochrome bc1 complex) [] and 5FI8 (P. falciparum dihydroorotate dehydrogenase)⁠ []. Next, the molecular target structures were represented according to the Swiss Model software [] for building the missing loops, and the resulting structures were submitted to H++3.0 [], a program that automates the key steps in the preparation of biomolecular structures for molecular modeling and simulations, as well as by the MGLTools ⁠software [] to assign the protonate state of histidines. In addition, a grid box was generated with dimensions of 20, 20, and 20 Å for both molecular targets. The coordinates of the grid box were centered on crystallographic ligands, 198.619, −25.603, and 81.313 Å for x, y, and z, respectively, for 4PD4, and −38.861, 102.656, and −15.221, for 5FI8, using the MGLTools software []. Subsequently, the HNQs and the FNQs structures were generated by the MarvinSketch⁠ program []. The protonation states and the tautomers, when possible, were adjusted according to pH 7.4 []. Next, all compound structures were refined by the Octopus software⁠ []. Octopus is an automated workflow management tool that integrates MOPAC2016⁠, MGLTools⁠, PyMOL⁠, and AutoDock Vina to perform molecular docking through a user-friendly interface [, –]. HNQs and FNQs were refined by the parametric method 7 (PM7) [] and the Eigenvector Following (EF) [] routine implemented in MOPAC2016 [] by the Octopus Run_mopac routine, which automatically assigns the total molecular charge for each ligand and checks for errors in the structures. The AutoDock Vina methodology was evaluated by redocking, and its exhaustiveness parameter was set to 24 to achieve more accurate results []. The figures were generated by academic versions of the Discovery Studio 4.5 program []. […]

Pipeline specifications

Software tools Marvin, MOPAC, PyMOL, AutoDock Vina
Applications Drug design, Protein interaction analysis
Organisms Plasmodium falciparum
Diseases Drug-Related Side Effects and Adverse Reactions
Chemicals Chloroquine, Naphthoquinones, Lactic Acid