Computational study of selected antimalarial and anticancer acylphloroglucinols

Abstract

Malaria and cancer tend to become drug-resistant few years after a drug is introduced into clinical use. This prompts the search for new molecular structures that are sufficiently different from the drugs for which resistance has developed. Acylphloroglucinols (ACPLs) are natural compounds with several biological activities. They are considered as possible lead structures for developing drugs against degenerative and other diseases. Computational studies are particularly important for biologically active compounds because their activities depend on their molecular properties, and knowing these properties (descriptors) is necessary for drug development. Representative ACPLs with anticancer and/or antimalarial activities were selected and computationally studied in vacuo and in three solvents with different polarities. All the calculations were done with completely relaxed geometry, using the Hartree Fock (HF) and Density Functional Theory (DFT) methods; second-order Moller-Plesset perturbation theory (MP2) calculations were also performed in vacuo. Structure-based virtual screening was used to study the interactions between these molecules and relevant proteins. The conformational studies identified conformational preferences and conformers’ stabilizing factors, among which intramolecular hydrogen bonds (IHBs) have dominant roles. The highest-occupied molecular orbital (HOMO) - lowest-unoccupied molecular orbital (LUMO) energy gap decreases and the dipole moment increases as the medium polarity increases. The solvent effect depends on the conformer type and the solvent polarity. The molecular docking analysis shows that most of these compounds bind well with the selected proteins and highlights the type of molecule-protein interactions for each case. These results indicate that the selected molecules are interesting for further steps in view of their possible development into antimalarial and anticancer drugs.