Using multiscale molecular modeling to analyze possible NS2b-NS3 protease inhibitors from medicinal plants endemic to the Philippines

Philippine folkloric medicinal plants like Euphorbia hirta (locally known as tawa-tawa), Carica papaya (papaya), Psidium guajava (guava), and Momordica charantia (bittermelon) have been used as a treatment for dengue. However, limited studies have been conducted regarding the extensive effects of these plants, especially their anti-dengue activity. This study evaluated 2,944 ligands from phytochemicals found in various medicinal plants as potential dengue inhibitors that could be developed into cost-effective and efficient therapeutic agents. SwissADME and Chembioserver online servers were used to conduct tests on absorption, distribution, metabolism, excretion, and toxicity (ADMET) for all ligands, resulting in 1,265 compounds being pharmacologically viable. By targeting the NS2b-NS3 protease of the dengue virus, specifically its catalytic triad of Asp 75, Ser 135, and His 51 residues, we can inhibit the replication of the virus. Molecular docking results showed ten ligands with comparable docking scores to the reference compounds. Attachment to the binding site is strengthened by electrostatic, polar, and hydrophobic interactions and the formation of hydrogen bonds. Furthermore, we also evaluated their stability using molecular dynamics simulations on GROMACS 2021.3. Molecular dynamics simulations of up to 100 ns of chemical time suggest eight of the ten candidate ligands are stable while binding to the active site. Free energy calculations using molecular mechanics Poisson-Boltzmann surface area also proved that six of the eight stable ligands exceeded the binding energies of the reference compounds. Results showed that veramiline from Veratrum mengtzeanum (pimacao), etiolin from Lilion martagon (Turks cap lily), hydroxyverazine from Eclipta prostrata (false daisy), chlorogenin from Yucca gloriosa (palm lily), cyclobranol from Euphorbia hirta (tawa-tawa), and ecliptalbine from Eclipta alba maintained their structural stability throughout the simulations. They also displayed good oral bioavailability and potential drug-like characteristics. These six compounds warrant further in vitro and in vivo investigation as potential dengue therapies.