title: Molecular structure-affinity relationship of bufadienolides and human serum albumin in vitro and molecular docking analysis.
abstract: The development of bufadienolides as anti-tumor agents is limited due to poor pharmacokinetic properties regarding drug half-lives and toxicity in vivo. These serious factors might be improved by increasing the drug/albumin-binding ratio. This study therefore investigated the relationship between the structural properties of nine bufadienolides and their affinities for human serum albumin (HSA) by a fluorescence spectroscopy-based analysis and molecular docking. Fluorescence quenching data showed that the interaction of each bufadienolide with HSA formed a non-fluorescent complex, while thermodynamic parameters revealed negative ΔS and ΔH values, corresponding to changes in enthalpy and entropy, respectively. The structural differences between the various bufadienolides markedly influenced their binding affinity for HSA. With the exception of a C = O bond at the C12 position that decreased the binding affinity for HSA, other polar groups tended to increase the affinity, especially a hydroxyl (OH) group at assorted bufadienolide sites. The rank order of binding affinities for drugs with tri-hydroxyl groups was as follows: 11-OH > 5-OH > 16-OH; in addition, 16-acetoxy (OAc), 10-aldehyde and 14-epoxy constituents notably enhanced the binding affinity. Among these groups, 11-OH and 16-acetyl were especially important for a seamless interaction between the bufadienolides and HSA. Furthermore, molecular docking analysis revealed that either an 11-OH or a 16-OAc group spatially close to a five-membered lactone ring significantly facilitated the anchoring of these compounds within site I of the HSA pocket via hydrogen bonding (H-bonding) with Tyr150 or Lys199, respectively. In summary, bufadienolide structure strongly affects binding with HSA, and 11-OH or 16-OAc groups improve the drug association with key amino acid residues. This information is valuable for the prospective development of bufadienolides with improved pharmacological profiles as novel anti-tumor drugs.
authors.affiliation: Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, PR China; Gansu University of Traditional Chinese Medicine, Lanzhou, PR China.
authors.forename: Guodi
authors.initials: G
authors.lastname: Lu
authors.affiliation: Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, PR China.
authors.forename: Honglan
authors.initials: H
authors.lastname: Wang
authors.affiliation: College of Basic Medicine, Nanjing University of Chinese Medicine, Nanjing, PR China.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, PR China.
authors.forename: Jinao
authors.initials: J
authors.lastname: Duan
authors.affiliation: Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, PR China.
authors.forename: Hongyue
authors.initials: H
authors.lastname: Ma
authors.affiliation: Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, PR China.
authors.forename: Qinan
authors.initials: Q
authors.lastname: Wu
mesh_terms: D000664:Amphibian Venoms / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism*; D001665:Binding Sites / Q000502:physiology; D002018:Bufanolides / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012709:Serum Albumin / Q000378:metabolism*; D013050:Spectrometry, Fluorescence; D013816:Thermodynamics
chemical_list: D000664:Amphibian Venoms; D000970:Antineoplastic Agents; D002018:Bufanolides; D012709:Serum Albumin