Caco-2: Predicting drug permeability and relationship with COVID-19 infected Caco-2 cells
Clifford W Fong · HAL (Le Centre pour la Communication Scientifique Directe) · 2021
Detailed studies of the permeability of a very wide range of drugs into Caco-2 cells shows thatactive transport, passive transcellular and passive paracellular transport can be separatelyidentified using the LFER method involving ΔGdesolv,CDS, ΔGlipo,CDS (both octane and octanol),dipole moment,molecular volume,and HOMO-LUMO gap. Active transport is dependent on theHOMO-LUMO energy gap. Transcellular passive permeability shows dependency on the cellmembrane lipophilicity as measured by ΔGlipo,CDS in n-octanol and the free energy of waterdesolvation ΔGdesolv,CDS. Paracellular passive permeability shows dependency on the molecularvolume in water. There is evidence that different Caco-2 cell lines in various literaturepermeability studies can result in varying contributions of active and passive transport modes fora given range of drugs.Inhibition of SARS-CoV-2 infected Caco-2 cells can be studied using the LFER method toseparate Caco-2 cell entry processes involving ACE2, TMPRSS2 or S-RBD from intracellularinhibitory processes. The extensive study by Ellinger [25] likely involves the inhibition of Caco-2 cell entry processes involving ACE2, TMPRSS2 or S-RBD. It is known that Caco-2 cells werethe only human cell type of 13 tested refractory cell lines that supported efficient SARS-CoVreplication and expression of the SARS-CoV receptor, ACE2, [38] and Chu [39] found bothhuman Calu-3 cells and Caco-2 cells were best suited for studying SARS-CoV-2 replication.Ellinger’s data for Caco-2 cells is a valuable source for evaluating the efficacy of SARS-CoV-2therapeutics.The in vitro IC50 and docking binding energies of SARS-CoV-2 inhibition of Mpro, ACE2, SRBD,TMPRSS2 show that the overwhelming conclusion is that the HOMO, or LUMO or theHOMO-LUMO energy gap is the principal determinant of inhibition of Mpro, S-RBD, ACE2 andTMPRSS2. The exception to this rule is the inhibitory binding to the human {ACE2-S-RBD}combined receptor which is likely to be a result of counterposing contributions from inhibitorHOMO àreceptorLUMO or receptorHOMO à inhibitorLUMO dominated interactions for both S-protein andACE2.