Discovery of dual-target natural antimalarial agents against DHODH and PMT of Plasmodium falciparum: pharmacophore modelling, molecular docking, quantum mechanics, and molecular dynamics simulations.

Malaria is a lethal disease that claims thousands of lives worldwide annually. The objective of this study was to identify new natural compounds that can target two P. falciparum enzymes; P. falciparum Dihydroorotate dehydrogenase (PfDHODH) and P. falciparum phosphoethanolamine methyltransferase (PfPMT). To accomplish this, e-pharmacophore modelling and molecular docking were employed against PfDHODH. Following this, 1201 natural compounds with docking scores of ≤ -7 kcal/mol were docked into the active site of the second enzyme PMT. The top nine compounds were subjected to further investigation using MM-GBSA free binding energy calculations and ADME analysis. The results revealed favourable free binding energy values better than the references, as well as acceptable pharmacokinetic properties. Compounds ZINC000013377887, ZINC000015113777, and ZINC000085595753 were scrutinized to assess their interaction stability with the PfDHODH enzyme, and chemical stability reactivity using molecular dynamics (MD) simulation and density functional theory (DFT) calculations. These findings indicate that the three natural compounds are potential candidates for dual PfDHODH and PfPMT inhibitors for malaria treatment.

Turning down PI3K/AKT/mTOR signalling pathway by natural products: an in silico multi-target approach.

The PI3K/AKT/mTOR pathway is a significant target for cancer drug discovery. Many efforts have focused on discovering new inhibitors against key kinase proteins involved in this pathway for cancer treatment. PI3K/mTOR dual inhibitors, such as PKI-179, have been reported to be more effective than agents that act only on a single protein target. The present computational study aimed to discover triple target inhibitors against PI3K, AKT, and mTOR proteins. Accordingly, the PI3K protein bound with the ligand was used as input for e-pharmacophore modelling to generate the pharmacophore hypothesis and then screened for a library of 270,540 natural products from the Zinc database resulting in 57,220 compounds that matched the hypothesis. These compounds were then docked into the active site of PI3K, resulting in 292 compounds with better docking scores than the co-crystallized ligand. These compounds were re-docked into AKT and mTOR proteins. Besides, MM-GBSA binding free energy calculations, MD simulations, and ADMET prediction were carried out, leading to 5 potential triple-target inhibitors namely, ZINC000014644152, ZINC000014760695, ZINC000014644839, ZINC000095099451, and ZINC000005998557. In conclusion, these inhibitors may be possible leads for inhibiting PI3K/AKT/mTOR pathway, and they may be further evaluated in vitro and clinically as anticancer agents.