Dynamics and Energetics of a Bromodomain in complex with bromosporine from Leishmania donovani; [Dinâmica e energética de um bromodomínio em complexo com bromospo-rina de Leishmania donovani]

Ropón-Palacios G.; Chenet-Zuta M.; Ramos-Galarza J.; Gervacio-Villarreal A.; Otazu K.; Cárdenas-Cárdenas R.; Casillas-Muñoz F. · Revista Colombiana de Quimica (2023) · DOI: 10.15446/rev.colomb.quim.v52n1.110374

Resumen

Leishmaniasis continues to be a neglected tropical disease, affecting people and animals and causing significant economic losses. Therefore, there is interest in the study and evaluation of new drug targets. In fact, it has been shown that by interfe-ring with lysine-reading proteins such as bromodomain (BMD) there is a decrease in parasite survival. In this study, we re-searched the dynamics and energetics of the Leishmania donovani BMD in complex with bromosporin, which is conside-red to be a pan-inhibitor of BMDs, with the aim of understanding the molecular recognition mechanism. Molecular dynamics (MD) and non-equilibrium free energy calculation guided by steered molecular dynamics (SMD) simulations showed that the BMD has three flexible amino acid regions and bromosporin exhibiting various recognition states during the in-teraction. These results corroborate the promiscuity of bromosporin for energeti-cally favourable sites, with the possibility of expanding its inhibition to other bro-modomains. Furthermore, these results suggest that Van der Waals interactions have more relevance for complex recognition and residues ASN-87 and TRP-93 are key in forming hydrophobic and H-bond interactions, respectively. This research provides new insights for understanding the recognition mechanism, dynamics and energetics of the complex for the development of new therapeutic strategies.

Instituciones: Universidad Nacional de la Amazonía Peruana; Universidad Nacional Tecnológica de Lima Sur