Design, molecular docking, ADME, and Molecular Dynamics studies of new 6-amino coumarin derivatives as carbonic anhydrase inhibitors

Abstract

New 6-amino coumarin derivatives were designed and computationally investigated as hCA IX
targeted compounds. Molecular docking, ADME prediction, and MD simulation were used to
study their expected interactions and physicochemical and pharmacokinetic characteristics.
ChemOffice was used to design the compounds' chemical structures, and GOLD was used to dock
them with hCA IX (PDB ID: 4M2V). The compounds have ChemPLP fitness ratings ranging from
67.98 to 76.88, indicating various interaction patterns in the hCA IX active site, such as hydrogen
bonding, short contacts, and interactions with the catalytic Zn²⁺ ion. Compounds 6c and 6e did not
show predicted coordination with the catalytic Zn²⁺ ion as predicted. SwissADME analysis found
no Lipinski criteria violations and gave preliminary ADME-related chemical characteristics. A 50
ns MD simulation of the selected the 6g–hCA IX complex demonstrated an initial conformational
adjustment and a steady RMSD profile later in the trajectory. The ligand-binding area showed low
variations, but surrounding regions showed more flexibility, according to RMSF analysis.
Computational results provide preliminary insights into the compounds' binding and
pharmacokinetic properties and assist their experimental research as possible hCA IX-targeted
therapies.