Caco-2: Predicting drug permeability and relationship with COVID-19 infected Caco-2 cells

Clifford W Fong (1)

1 Eigenenergy

Detailed studies of the permeability of a very wide range of drugs into Caco-2 cells shows that active transport, passive transcellular and passive paracellular transport can be separately identified 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 the HOMO-LUMO energy gap. Transcellular passive permeability shows dependency on the cell membrane lipophilicity as measured by ΔGlipo,CDS in n-octanol and the free energy of water desolvation ΔGdesolv,CDS. Paracellular passive permeability shows dependency on the molecular volume in water. There is evidence that different Caco-2 cell lines in various literature permeability studies can result in varying contributions of active and passive transport modes for a given range of drugs. Inhibition of SARS-CoV-2 infected Caco-2 cells can be studied using the LFER method to separate Caco-2 cell entry processes involving ACE2, TMPRSS2 or S-RBD from intracellular inhibitory 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 were the only human cell type of 13 tested refractory cell lines that supported efficient SARS-CoV replication and expression of the SARS-CoV receptor, ACE2, [38] and Chu [39] found both human 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-2 therapeutics. 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 the HOMO-LUMO energy gap is the principal determinant of inhibition of Mpro, S-RBD, ACE2 and TMPRSS2. 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 à receptorLUMO or receptorHOMO à inhibitorLUMO dominated interactions for both S-protein and ACE2.

Domaines: Chimie théorique et/ou physique; Chimie thérapeutique

Clifford W Fong. Caco-2: Predicting drug permeability and relationship with COVID-19 infected Caco-2 cells. [Research Report] Eigenenergy Adelaide South Australia. 2021. ⟨hal-03147823⟩