| Popis: |
It has been shown that a linear free energy relationship (LFER) can describe the structure activity of the inhibition of the main protease M pro of COVID-19 or SARS-Cov-2. Application of this LFER can be used to predictably rank the inhibitory efficacy of a series of repurposed drugs against the main protease of SARS-CoV-2, as well as SARS-CoV and MERS. The same LFER also applies to the intracellular accumulation of M pro inhibitors from the plasma and their inhibitory efficacy Cmax/EC90 in the targeted lung tissue. The LFER is linearly comprised of the desolvation energy, lipophilicity, dipole moment, molecular volume and HOMO-LUMO energy gap, with varying combinations of these fundamental molecular specifiers applying differently to various structural series of inhibitors. It is also shown that protonation of basic drugs has a major influence on bioavailability in the target lung tissue pH 6.7 compared to that in the plasma pH 7.4, with the major difference between the neutral species and the charged species is due to the differences in desolvation energy of the inhibitors. Neutral species passively penetrate the infected cell membrane, or endocytosis (which requires some degree of desolvation as the drug is engulfed by the lipophilic membrane) may be required to transport larger drugs across the cell membrane. There is evidence in the literature that molecular docking methods that derive binding energies to predict likely inhibitors of M pro of SARS-CoV-2 do not always correlate well with structure activity inhibitory studies of M pro. This study shows that the binding energy of a series of inhibitors is well correlated with the HOMO-LUMO energy gap and the molecular volume of the inhibitors. |
