Probing Passive Permeation of Tetracycline: Are Simulations Ready for beyond-Rule-of-Five Drug Permeability Calculation?

ABSTRACT: Passive permeation across lipid membranes is a key determinant of drug bioavailability and efficacy. Accurate computational estimation of drug permeability is essential for rational drug design, yet remains challenging, particularly for ionizable and beyond-Rule-of-Five (bRo5) compounds. In this study, we employ advanced molecular simulations and the inhomogeneous solubility-diffusion model to calculate the effective permeability and elucidate the membrane permeation mechanism of the antibiotic tetracycline (TC), the six hydrogen-bond donors of which violates one of Lipinski's Rule-of-Five. By integrating the pH-partitioning and Boltzmann-weighted average potential schemes and accounting for both its neutral (TC_N) and zwitterionic (TC_Z) tautomers, we show that the dom

SUBMITTER: Qi Y 

PROVIDER: S-EPMC12536400 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature