ABSTRACT
The diffusion of drugs into the cellular membrane is an important step in the drug delivery systems. Furthermore, predicting the interaction and permeability of drugs across the cellular membrane could help scientists to design bioavailable and high-efficient drugs. Discovering the COVID-19 drugs has recently drawn remarkable attention to tackle its outbreak. Due to the rapid replication of the coronavirus in the human body, searching for highly permeable drugs into the cellular membrane is vital. Herein, we performed the molecular dynamics (MD) simulation and density functional (DFT) calculations to investigate the permeability of keto and enol tautomers of the favipiravir (FAV) as well as hydroxychloroquine (HCQ) COVID-19 drugs into the cellular membrane. Our results reveal that though both keto and enol tautomers of the FAV are feasible to transfer through the cellular membrane, the keto form moves faster and diffuses deeper; however, the HCQ molecules aggregate in the water phase and remain near the cellular membrane. It is worth pointing out that the obtained results are consistent with the reactivity trends projected by the calculated reactivity descriptors of the considered drugs. Despite the pair correlation function and H-bond analyses revealing the interactions between the membrane and HCQ, the aggregation of the HCQ molecules resists their passage through the cellular membrane. Besides, the lower free energy barrier of FAV confirms its higher permeability than HCQ. These findings suggest that due to the deeper permeability of the FAV drug, its effectiveness can be more than that of HCQ. These molecular insights might help with a better understanding of the interactions between COVID-19 drugs and cellular membranes. Moreover, these theoretical findings could help experimental researchers find high-efficient strategies for COVID-19 therapy.