Study of interaction energies between residues of the active site of Hsp90 and geldanamycin analogues using quantum mechanics/molecular mechanics methods

Abstract

Heat shock protein (Hsp90KDa) is a molecular chaperone Background: involved in the process of cellular oncogenesis, hence its importance as a therapeutic target in clinical trials. Geldanamycin is an inhibitor of Hsp90 chaperone activity, which binds to the ATP binding site in the N-terminal domain of Hsp90. However, geldanamycin has shown hepatotoxic damage in clinical trials; for this reason, its use is not recommended. Taking advantage that geldanamycin binds successfully to Hsp90, many efforts have focused on the search for similar analogues, which have the same or better biological response and reduce the side effects of its predecessor; 17-AAG and 17-DMAG are examples of these analogues.In order to know the chemical factors influencing the growth or Methods: decay of the biological activity of geldanamycin analogues, different computational techniques such as docking, 3DQSAR and quantum similarity were used. Moreover, the study quantified the interaction energy between amino acids residues of active side and geldanamycin analogues, through hybrid methodologies and density functional theory (DFT) indexes.The evaluation of interaction energies showed that the interaction Results: with Lys58 residue is essential for the union of the analogues to the active site of Hsp90, and improves its biological activity. This union is formed through a substituent on C-11 of the geldanamycin macrocycle. A small and attractor group was found as the main steric and electrostatic characteristic that substituents on C11 need in order to interact with Lys 58; behavior was

New findings on ligand series used as SARS-CoV-2 virus inhibitors within the frameworks of molecular docking, molecular quantum similarity and chemical reactivity indices

“…Our research group has used several reactivity indices with Quantum Similarity. [26][27][28][29][30][31][32][33][34][35] The reactivity indices used in this work are chemical potential (μ), [36][37][38] hardness (ɳ), 39 and electrophilicity (ω), 38,39 which will be calculated.…”

New findings on ligand series used as SARS-CoV-2 virus inhibitors within the frameworks of molecular docking, molecular quantum similarity and chemical reactivity indices

“…{r 1 , r 2 } are sets of electronic coordinates related to the corresponding wave function, and the operator Ω (r 1 ,r 2 ) is positively defined and supported on the electronic coordinates. [22][23][24][25][26] Types of measurements in molecular quantum similarity…”

“…23,24 Chemical reactivity analysis Our research group has used several reactivity indices with Quantum Similarity. [26][27][28][29][30][31][32][33][34][35] The reactivity indices used in this work are chemical potential (μ), [36][37][38] hardness (ɳ), 39 and electrophilicity (ω), 38,39 which will be calculated.…”