Therapeutic Delivery Potential of Covalent Organic Framework (COF): Intuition from Theoretical Calculations

Abstract Regardless of the benefits, pharmaceutical companies are reticent to engage further in covalent organic framework‐based drug development and drug delivery systems, preferring rather to explore preexisting chemical compound libraries for drug delivery. As such, this study aims to account for the efficacy of covalent organic frameworks (COFs) in the delivery of seven conventional drugs: Acetaminophen, Clodronic Acid, Hydroxyurea, Mercaptoporine, Thiotepa, Tioguanine, and Arsenic trioxide. Herein, Gaussian 16 software package is employed for the purpose of optimizing the systems at the DFT/ωB97XD/def2svp level of theory. Substantially, the nature of the inter‐ and intra‐ molecular interactions between the COF and each of the drugs utilized resulted in the re‐adjustment of the molecular orbitals and yielded a distinct set of results for the most reactive and least stable and vice versa as deducible from the magnitudes of the highest occupied molecular orbital and lowest unoccupied molecular orbital (HOMO‐LUMO) gaps. Furthermore, the natural bond orbital (NBO) study indicates that the interacting molecules exhibit similar stability and reactivity, as evidenced by the proximity of their mean stabilization energies. Additionally, the topological analysis revealed that the most positive interaction occurred in Acetaminophen_COF, Clodronic acid_COF, Hydroxyurea_COF, and Tioguanine_COF. Also, the adsorption studies demonstrate that the above‐mentioned drugs have weak interaction kinetics when they interact with the investigated COF. Strong adsorbing contacts were detected in the interactions of Arsenic trioxide, Hydroxyurea, and Tioguanine with the COF in the order Arsenic trioxide_COF < Hydroxyurea_COF < Tiog_COF, with corresponding values of −9.413 kcal/mol, −12.550 kcal/mol, and −17.570 kcal/mol, respectively. Overall, the study hypothesizes that when delivering the various drugs studied through the COF to biological systems, Acetaminophen, Hydroxyurea, Tioguanine, and Mercaptopurine have high reactivity with the COF and would be better adsorbed on it, as well as a longer recovery time of desorption due to their high adsorption on the COF surface.