Computable properties of selected monomeric acylphloroglucinols with anticancer and/or antimalarial activities and first-approximation docking study.

Context: Malaria and cancer tend to become drug-resistant a 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. The present work considers eight selected acylphloroglucinols (ACPLs) with proven antimalarial and/or anticancer activities. ACPLs are compounds of natural origin structurally derivative from 1,3,5-trihydroxybenzene and characterized by the presence of an acyl group R-C = O. The selected ACPLs contain only one acylphloroglucinol moiety and are, therefore, monomeric ACPLs (also occasionally called "simple" ACPLs). They were studied computationally in vacuo and in-three-solvents with different polarities, using different levels of theory. The findings on molecular properties relevant to the understanding of biological activities align with previous studies, enhancing the reliability of predictions for molecules of the same class and providing insights into their behaviour in different environments. Structure-based virtual screening was used to study the interactions between these molecules and selected proteins known as relevant drug targets for antimalarial and anticancer activities; the screening showed that most of these ACPLs bind well with the selected proteins, thus being interesting for further studies. The results also suggest that most of these ACPLs have the potential for dual therapeutic applications (antimalarial and anticancer), offering a cost-effective drug development option. Furthermore, the ADME-T predictions indicated favourable pharmacokinetic properties for these ACPLs.

Methods: Computational studies of the selected ACPLs were performed using Gaussian-09, in vacuo and in-three-solvents with different polarities. Three different levels of theory were used - Hartree Fock (HF), Density Functional Theory (DFT) with the B3LYP functional, and second order Møller-Plesset Perturbation Theory (MP2). HF and MP2 used a 6-31G(d,p) basis set, while DFT used a 6-31G + (d,p), for consistency with previous studies on ACPLs. The investigated molecular properties include conformational preferences, intramolecular hydrogen bonding patterns, HOMO-LUMO energy gap, dipole moments, as well as the solvent effect for the three considered solvents. Virtual screening was conducted using the Schrödinger suite, including Maestro 9.3 with GLIDE for docking and GlideScore for evaluating binding affinities. In addition, the QikProp tool provided ADME-T predictions for pharmacokinetic properties.