Wydział Chemii

Kamil Wojtkowiak

Mariusz Michalczyk

Wiktor Zierkiewicz

Aneta Jezierska

Jarosław J. Panek

2022

International Journal of Molecular Sciences

23

13701/1-13701/20

10.3390/ijms232213701

Naukowa

Angielski

Artykuł

It is postulated that the overexpression of Carbonic Anhydrase isozyme IX in some cancers contributes to the acidification of the extracellular matrix. It was proved that this promotes the growth and metastasis of the tumor. These observations have made Carbonic Anhydrase IX an attractive drug target. In the light of the findings and importance of the glycoprotein in the cancer treatment, we have employed quantum–chemical approaches to study non-covalent interactions in the binding pocket. As a ligand, the acetazolamide (AZM) molecule was chosen, being known as a potential inhibitor exhibiting anticancer properties. First-Principles Molecular Dynamics was performed to study the chalcogen and other non-covalent interactions in the AZM ligand and its complexes with amino acids forming the binding site. Based on Density Functional Theory (DFT) and post-Hartree–Fock methods, the metric and electronic structure parameters were described. The Non-Covalent Interaction (NCI) index and Atoms in Molecules (AIM) methods were applied for qualitative/quantitative analyses of the non-covalent interactions. Finally, the AZM–binding pocket interaction energy decomposition was carried out. Chalcogen bonding in the AZM molecule is an important factor stabilizing the preferred conformation. Free energy mapping via metadynamics and Path Integral molecular dynamics confirmed the significance of the chalcogen bond in structuring the conformational flexibility of the systems. The developed models are useful in the design of new inhibitors with desired pharmacological properties.

Carbonic Anhydrase IX mimic, acetazolamide, non-covalent interactions, binding pocket, METD, DFT, SAPT, CPMD, PIMD

CC-BY

http://dx.doi.org/10.3390/ijms232213701

http://www.mdpi.com/journal/metals