Malaria is one of the neglected diseases, and according to WHO it affects approximately 214 million people around the world. In addition to being an aggressive disease, the drugs used are scarce, have severe adverse effects and are often ineffective due to the development of parasite resistance mechanisms. In addition to these factors, difficulties in P&D of new drugs, due to pharmacokinetic and bioavailability limitations of antimalarial candidates, are difficult for the development of therapeutically useful new drugs. In this context, this work was aimed at using in silico studies of ADMET and molecular docking to predict pharmacokinetic parameters, and the interaction of acridine derivatives with the enzyme Dihydrofolate reductase (DHFR-TS) of P.falciparum. For the ADMET study was using the SwissADME free software. For the docking, the enzyme PfDHFR-TS (PDB code id: 4DPD) was chosen, and the acridine derivatives published in the paper by PEREIRA (2016) were used as binders. Molecular docking was performed by the Moqueiro Virtual Docking 6.0 program, in which the protein was optimized and the compounds were submitted to molecular coupling after optimization of the geometry. The results indicate that all derivatives have desirable molecular properties for a new drug, as well as indicate good gastrointestinal absorption (TPSA ≤ 140 Å2) and bioavailability. The molecules studied have the potential to inhibit the CYP2C19, CYP2C9 and CYP3A4 isoforms, however, none of them possibly interact with the P-gp protein. Molecular docking results indicate that all compounds showed negative binding energy, with AC-10 being the best result, indicating the possibility of stable interactions with the enzyme PfDHFR-TS, which is responsible for the resistance of P. falciparum to many antiamalarials agents.
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Antimalarial acridine N-acylidrazonic derivatives: ADME in silico studies and molecular
Published: 25 October 2018 by MDPI in MOL2NET'18, Conference on Molecular, Biomed., Comput. & Network Science and Engineering, 4th ed. congress CHEMBIOMOL-04: Chem. Biol. & Med. Chem. Workshop, Paraiba, Porto, Rostock, Germany-Galveston, Texas, USA, 2018
Keywords: malaria; acridine derivatives; ADMET; molecular docking; in silico studies