Interaction of novel Aurora kinase inhibitor MK-0457 with human serum albumin: Insights into the dynamic behavior, binding mechanism, conformation and esterase activity of human serum albumin.

In-vitro assessment of the binding properties of MK-0457, a novel Aurora kinase inhibitor, with human serum albumin: computer simulations in combination with multi-spectroscopic, esterase activity and microscopic studies. • MK-0457 bound to site 2 via vander Waals and hydrogen bonds. • Multispectroscopic comfirmed the binding was initiated by static quenching type. • MK-0457 could perturb the helicity of HSA and induce its conformational changes. • The esterase activity of HSA was decreased upon MK-0457 binding. • The morphology of HSA changed induced by interactions with MK-0457. MK-0457, a new pan-aurora kinase inhibitor, is in Phase II clinical development for the treatment of multiple tumor types and hematologic malignancies. The present work explored the dynamic behaviors and interaction mechanism of MK-0457 to human serum albumin (HSA) and the effect on the esterase-like activity and conformation of HSA by computer simulations and experiments. Docking and molecular dynamics trajectory analysis indicated that MK-0457 stably bound to Sudlow's site 2 of HSA by multiple types of interaction forces. Competitive experiments further verified MK-0457 was bound at first to Sudlow's site 2 and then the excess of drug was bound to Sudlow's site 1. The steady-state fluorescence combined with ultraviolet–visible absorption and fluorescence lifetime measurements specified a static quenching mechanism with association constants of 104 M−1 reflecting moderate binding affinity of MK-0457 for HSA. The analysis of R g values showed that the structure of HSA became loose due to MK-0457 binding, inducing slight conformational changes of HSA, which was consistent with the results obtained from circular dichroism, synchronous, and 3D fluorescence spectroscopy. The esterase-like activity of HSA showed that MK-0457 inhibits the catalytic activity of subdomain IIIA of HSA by binding to the vital residues TYR411. Atomic force microscopy images indicated that MK-0457 affects the molecular sizes of HSA by transforming the morphology of HSA from aggregation diploids to small monomers. This study is beneficial for understanding the biological action of MK-0457, providing additional information about the feasibility of its transport and accumulation in blood plasma. [ABSTRACT FROM AUTHOR]