Docking, steered molecular dynamics, and QSAR studies as strategies for studying isoflavonoids as 5-, 12-, and 15-lipoxygenase inhibitors

<p>Lipoxygenases (LOX) are enzymes that catalyze polyunsaturated fatty acid peroxidation and have a non-heme iron atom located in their active site. They are implicated in the arachidonic acid pathway and involved in inflammation, fever, pain production, and in the origins of several diseases such as cancer, asthma, and psoriasis. The search for inhibitors of these enzymes has emerged in the last years, and isoflavonoids have a broad spectrum of biological activity with low cytotoxicity. Our previous results have shown that isoflavonoids inhibited different LOX isoforms <i>in vitro</i>. For this reason, we studied the most important interactions that govern the potency and selectivity of some isoflavones and isoflavans toward different LOX isoforms using computational methods. The docking results have shown that all the molecules can be located in different zones in the LOX active site. Steered molecular dynamics indicated that selectivity was present at the cavity entry, but not at its exit. We also observed the correlation between the potential mean force and the best (HIR-303) and worst inhibitors (IR-213) in 5-LOX. Finally, structure–activity relationship (QSAR) studies showed a good correlation between theoretical IC₅₀ values and experimental data for 5-LOX and 12-LOX with 96 and 95%, respectively, and a lower correlation for 15-LOX (79%). Conclusively, pharmacophore analysis showed that our proposed molecules should possess a donor–acceptor and aromatic centers to encourage interactions in the active site.</p

Structural analysis and molecular docking of trypanocidal aryloxy-quinones in trypanothione and glutathione reductases: a comparison with biochemical data

<p>A set of aryloxy-quinones, previously synthesized and evaluated against <i>Trypanosoma cruzi</i> epimastigotes cultures, were found more potent and selective than nifurtimox. One of the possible mechanisms of the trypanocidal activity of these quinones could be inhibition of trypanothione reductase (TR). Considering that glutathione reductase (GR) is the equivalent of TR in humans, biochemical, kinetic, and molecular docking studies in TR and GR were envisaged and compared with the trypanocidal and cytotoxic data of a set of aryloxy-quinones. Biochemical assays indicated that three naphthoquinones (<b>Nq-h</b>, <b>Nq-g</b>, and <b>Nq-d</b>) selectively inhibit TR and the TR kinetic analyses indicated that <b>Nq-h</b> inhibit TR in a noncompetitive mechanism. Molecular dockings were performed in TR and GR in the following three putative binding sites: the catalytic site, the dimer interface, and the nicotinamide adenine dinucleotide phosphate-binding site. In TR and GR, the aryloxy-quinones were found to exhibit high affinity for a site near it cognate-binding site in a place in which the noncompetitive kinetics could be justified. Taking as examples the three compounds with TR specificity (TRS) (<b>Nq-h</b>, <b>Nq-g</b>, and <b>Nq-d</b>), the presence of a network of contacts with the quinonic ring sustained by the triad of Lys62, Met400′, Ser464′ residues, seems to contribute hardly to the TRS. Compound <b>Nq-b</b>, a naphthoquinone with nitrophenoxy substituent, proved to be the best scaffold for the design of trypanocidal compounds with low toxicity. However, the compound displayed only a poor and non-selective effect toward TR indicating that TR inhibition is not the main reason for the antiparasitic activity of the aryloxy-quinones.</p