(5,6) However, with a few exceptions, they are generally not able to cross through the cell membrane. (4) Biologics, such as antibodies, are the prime class of pharmaceuticals to target extracellular PPIs with uncontested specificities and affinities. (3) A major portion of these yet undruggable targets are intracellular protein–protein interfaces (PPIs), including several notorious cancer-associated targets. (1,2) Approximately 75% of disease relevant proteins still cannot be targeted, neither with small molecules nor with biopharmaceuticals. Macrocycles are a potent new class of molecules for drug discovery. We thus recommend this purely physics-based approach as a computational tool to assess cell permeabilities of macrocyclic drug candidates. For the studied model systems, we find that the transfer free energy exceeds the purely water-based solvation free energies as a reliable estimate of cell permeability and that conformational sampling is imperative for a physically meaningful model. Following this strategy, we find a striking correlation of 0.92 between experimentally determined cell permeabilities and calculated transfer free energies. Hence, the proposed method considers how the conformational diversity of macrocycles in polar and apolar solvents translates into transfer free energies. Subsequent GIST calculations facilitate a quantitative measure of solvent preference in the form of a transfer free energy, calculated from the ensemble-averaged solvation free energies in water and chloroform. We perform accelerated molecular dynamics simulations to capture a diverse structural ensemble in water and chloroform, allowing for a direct profiling of solvent-dependent conformational preferences. #Auto clicker by polar 2.1 free download seriesHere, we employ grid inhomogeneous solvation theory (GIST) to calculate solvation free energies for a series of six macrocycles in water and chloroform as a measure of passive membrane permeability. The relation of surface polarity and conformational preferences is decisive for cell permeability and thus bioavailability of macrocyclic drugs.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |