Chalcogen Bond as a Factor Stabilizing Ligand Conformation in the Binding Pocket of Carbonic Anhydrase IX Receptor Mimic

Abstract

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.

Progress of Section “Biochemistry” in 2022

“…A relevant number of papers dealing with this enzyme, its inhibitors, activators and involvement in various diseases have been published in 2022 in this journal [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. The first group of contributed materials dealt with the use of this protein for investigations of basic biochemical approaches, such as protein folding [ 7 ], thermodynamic parameters assessment for protein–ligand interactions [ 8 ], bioluminescence resonance energy transfer connected to the binding of the metal ion to apoenzymes [ 9 ], the possibility to evidence chalcogen bonds in the X-ray crystal structures of CA–lig and adduct [ 10 ]. In two other papers, the role of CAs in CO 2 sequestration processes for alleviating global warming [ 11 ] or in photosynthesis in bacteria and plants (only the α-class CAs were considered in a very informative review by De Simone’s group [ 12 ]) were thoroughly discussed, proving again the potential environmental applications of these enzymes.…”

Unraveling the Nature of Hydrogen Bonds of “Proton Sponges” Based on Car-Parrinello and Metadynamics Approaches

“…In order to describe the quantum nature of nuclei, Path Integral Molecular Dynamics (PIMD) was developed [ 6 , 35 ]. The method was successfully applied in our numerous studies of intra- and intermolecular interactions [ 23 , 36 , 37 ].…”

Understanding the Exchange Interaction between Paramagnetic Metal Ions and Radical Ligands: DFT and Ab Initio Study on Semiquinonato Cu(II) Complexes

“…It is now well established that theoretical methods are an efficient multipurpose tool for chemistry, biochemistry, and material science. Recent scientific efforts have shown that they can help us understand various phenomena, for example, reaction mechanisms or reactivity [ 35 , 36 , 37 , 38 ], electron density distribution [ 39 , 40 , 41 ], and elusive structure of complex biochemical systems or radical centers [ 42 , 43 , 44 ], anticancer [ 35 , 45 ] and antioxidant properties [ 46 , 47 , 48 , 49 , 50 , 51 ], soot formation [ 52 ] or pesticide decomposition [ 53 ]. The exchange coupling between paramagnetic centers has been a subject of such investigations at the density functional theory (DFT) and ab initio levels, but these studies were mainly limited to the interaction between metallic centers [ 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 ].…”