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

Abstract

Background: Heat shock protein (Hsp90KDa) is a molecular chaperone involved in the process of cellular oncogenesis, hence its importance as a therapeutic target. 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. Methods: In order to know the chemical factors influencing the growth or 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 methodology (Autodock-PM6) and DFT indexes. Results: The evaluation of interaction energies showed that the interaction 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 observed with hydroxy and methoxy series of geldanamycin analogues, under study. Conclusion: This study contributes with new hybrid methodology (Autodock-PM6) for the generation of 3DQSAR models, which to consider the interactions between compounds and amino acids residues of Hsp90´s active site in the alignment generation. Additionally, quantum similarity and reactivity indices calculations using DFT were performed to know the non-covalent stabilization in the active site of these compounds.

Keywords: 3D-QSAR; Hsp90; Molecular Quantum Similarity.; PM6; QM/MM approach; geldanamycin analogues.

Figure 1.. Structure of geldanamycin.

The carbon atom C-11 and C-17s of the macrocycle of the geldanamycin are numerically indicated.

Figure 2.

a) R ³ indicates the position that takes the substituents on the C-11 position of the macrocycle for the analogues of series 7 and b) Structure bioactive of the 17-DMAG.

Figure 3.. Structure of the geldanamycin macrocycle maintained as rigid during molecular dynamics.

Figure 4.. Alignment used to obtain 3DQSAR model A.

Figure 5.. Alignment used for models 3DQSAR B and C, respectively.

Figure 6.

( a) Steric map and ( b) electrostatic map on positions C-11 and C-17 (CoMFA).

Figure 7.. Interaction energies of geldanamycin.

Red arrows show the energy interaction values of Lys58, Asp93 and Lys112 residues.

Figure 8.. Possible interactions between residues of the active site of Hsp90 and geldanamycin.

Green lines indicate the residues donator of hydrogen bridge.

Figure 9.. Interaction energies of geldanamycin analogues 2, 3e, 4b, 6 d, 8 h, 8i and geldanamycin.

Figure 10.. Interaction energies of 11-hydroxy analogues and geldanamycin.

Figure 11.. Interaction energies of 11-methoxy geldanamycin analogues.

Figure 12.. Interaction energies of 11-O-acyl geldanamycin analogues.

Figure 13.. Interaction energies of 11-ketone geldanamycin analogues.

Figure 14.. Interaction energies of 11-amine geldanamycin analogues.

Figure 15.. Interaction energies of 11-oxime geldanamycin analogues.

Figure 16.. Comparison of the interaction energies of geldanamycin and analog 2.

Figure 17.. Frontier molecular orbitals HOMO, LUMO (isosurface 0.02), the Fukui Functions 〈fk−〉≈|HOMO|2 and 〈fk+〉≈|LUMO|2 (isosurface 0.004), to compound 1a.

Figure 18.. Frontier molecular orbitals HOMO, LUMO (isosurface 0.02), the Fukui Functions 〈fk−〉≈|HOMO|2 and 〈fk+〉≈|LUMO|2 (isosurface 0.004), to reference compound GDM.

Figure 19.. Frontier molecular orbitals HOMO, LUMO (isosurface 0.02), the Fukui Functions 〈fk−〉≈|HOMO|2 and 〈fk+〉≈|LUMO|2 (isosurface 0.004), to reference compound 2.