In silico evaluation of pharmacokinetic parameters, delivery, distribution and anticoagulative effects of new 4,7-dihydroxycoumarin derivative

In this study, pharmacological profiling and investigation of the anticoagulant activity of the newly synthesized coumarin derivative: (E)-3-(1-((4-hydroxy-3-methoxyphenyl)amino)ethylidene)-2,4-dioxochroman-7-yl acetate (L) were performed. The obtained results were compared with the parameters obtained for Warfarin (WF), which is a standard good oral anticoagulant. The estimated high binding affinity of L toward plasma proteins (PPS% value is > 90%) justifies the investigation of binding affinity and comparative analysis of L and WF to Human Serum Albumin (HSA) using the spectrofluorimetric method (296, 303 and 310 K) as well as molecular docking and molecular dynamics simulations. Compound L shows a very good binding affinity especially to the active site of WF (the active site I -subdomain IIA), quenching HSA fluorescence by a static process. Also, the finite element smeared model (Kojic Transport Model, KTM), which includes blood vessels and tissue, was implemented to compute the convective-diffusion transport of L and WF within the liver. Finally, compound L shows a high degree of inhibitory activity toward the VKOR receptor comparable to the inhibitory activity of WF. Stabilization and limited flexibility of amino acid residues in the active site of the VKOR after binding of L and WF indicates a very good inhibitory potential of compound L. The high affinity of the L for the VKOR enzyme (Vitamin K antagonist), as well as the structural similarity to commercial anticoagulants (WF), provide a basis for further studies and potential application in the treatment of venous thrombosis, pulmonary embolism and ischemic heart disease.

Communicated by Ramaswamy H. Sarma