Mechanism of Inhibition of Hsp90 Dimerization by Gyrase B Inhibitor Coumermycin A1 (C–A1) Revealed by Molecular Dynamics Simulations and Thermodynamic Calculations

Abstract

Heat shock protein (Hsp) 90 an emerging and attracting target in the anti-HIV drug discovery process due to the key role it plays in the pathogenicity of HIV-1 virus. In this research study, long-range all-atom molecular dynamics simulations were engaged for the bound and the unbound proteins to enhance the understanding of the molecular mechanisms of the Hsp90 dimerization and inhibition. Results evidently showed that coumermycin A1 (C-A1), a recently discovered Hsp90 inhibitor, binds at the dimer's active site of the Hsp90 protein and leads to a substantial parting between dimeric opposed residues, which include Arg591.B, Lys594.A, Ser663.A, Thr653.B, Ala665.A, Thr649.B, Leu646.B and Asn669.A. Significant differences in magnitudes were observed in radius of gyration, root-mean-square deviation and root-mean-square fluctuation, which confirms a reasonably more flexible state in the apo conformation associated with it dimerization. In contrast, the bound conformer of Hsp90 showed less flexibility. This visibly highpoints the inhibition process resulting from the binding of the ligand. These findings were further validated by principal component analysis. We believe that the detailed dynamic analyses of Hsp90 presented in this study, would give an imperative insight and better understanding to the function and mechanisms of inhibition. Furthermore, information obtained from the binding mode of the inhibitor would be of great assistance in the design of more potent inhibitors against the HIV target Hsp90.

Structural Basis for DNA Gyrase Interaction with Coumermycin A1

“…Aminocoumarins have been shown to interact with other ATP-binding GHKL fold-containing proteins and in particular the eukaryotic heat shock protein Hsp90, , an emerging target in anticancer therapies. COU inhibits Hsp90 10-fold greater than novobiocin . Furthermore, new COU analogues have been reported to harbor antiproliferative activity and IC 50 values against Hsp90 100-fold more potent than the natural molecule .…”

Synthesis of Chromeno[3,4-b]piperazines by an Enol-Ugi/Reduction/Cyclization Sequence

“…We have recently reported the effective multicomponent enol-Ugi condensation of enols (15), aldehydes (12), amines (13) and isocyanides (14) leading to polysubstituted heterocyclic enamines (17; Scheme 2) [49][50][51]. The enol-Ugi condensation of 4-hydroxy-3nitro-coumarin (15) and cyclohexyl isocyanide (14a) with different amines (13a-d) and aldehydes (12a-e) or the corresponding preformed imines (16a-k) leads to aminoacylcoumarins (17a-k) in good to excellent yields (Table 1). a Procedure for the synthesis of 17a-k: Isocyanide 14 (1 equiv) and enol 15 (1 equiv) were added to a solution of imine 16 (1 equiv) in CH2Cl2 and stirred at 20 °C for 3 h. b Procedure for the synthesis of 19a-i and 18j,k: Enol-Ugi adduct 17 (1 equiv) and iron powder (24 equiv) were stirred at rt for 2-4 h. c The reaction was performed at 150 °C.…”

“…Among the most attractive rigid peptidic scaffolds for drug discovery are piperazines [ 5 , 6 , 7 , 8 , 9 , 10 ], which are present in many alkaloids and pharmaceuticals that can bind to a wide range of receptors [ 11 ]. Additionally, 3-aminocoumarins are considered privileged structures, present in various biologically active natural didepsipeptides, such as bacterial antibiotics novobiocin [ 12 , 13 , 14 ], coumermycines [ 15 ] and cacibiocins [ 16 ], and marine-derived fungal metabolites trichodermamides [ 17 , 18 , 19 ].…”

Molecular Approaches to Protein Dimerization: Opportunities for Supramolecular Chemistry

“…Rapamycin is thus capable of inducing heterodimerization of fusion proteins featuring FKBP and FRB domains. In contrast to rapamycin, coumermycin has two of the same protein-binding moieties and can be used to induce homodimerization of GyrB (bacterial DNA gyrase B) ( Farrar et al, 1996 ; Farrar et al, 2000 ; Cele et al, 2016 ; Broeck et al, 2019 ). The concept of molecule glue-induced protein dimerization can be extended to novel synthetic compounds as well.…”