Insight into the delivery channel and selectivity of multiple binding sites in bovine serum albumin towards naphthalimide-polyamine derivatives

Naphthalimide derivatives are types of small-molecule anticancer drug candidates; however, their negative factors and potential side effects make their application limited. The pharmacophores select a direct access into the tumor cells as the first choice; this can reduce the side effect of the anti-cancer drugs on the normal cells. Herein, the delivery and binding of the naphthalimide-polyamine complex assisted by the bovine serum albumin (BSA) protein have been studied by combining several molecular dynamic simulations. The plausible transportation channels and the most favorable pathways for the delivery of the naphthalimide-polyamine complex to two drug sites (DSI and DSII), their thermodynamic and dynamic properties and the mechanisms have been discussed in detail. The residues His287 and Phe394 acted as guards in the DSI and DSII, respectively, which played a gating-switch role by flipping the ring from open to close during the compound delivery. The binding mode, binding energy and substituent effects have been also identified. The two drug sites have different preferences towards the compound with the electron-withdrawing and electron-donating substituents, and their strong interactions are more sensitive to the number of the substituent groups. The naphthalimide-polyamine complexes are more likely to choose DSI, both thermodynamically and dynamically, as compared to DSII. This selective specificity of these two drug sites manipulated by the electron-withdrawing and electron-donating substituents is quite promising for the design of new naphthalimide drugs.