title: Spectroscopic studies and molecular docking on the interaction of organotin antitumor compound bis[2,4-difluoro-N-(hydroxy-⟨κ⟩O)benzamidato-⟨κ⟩O]diphenyltin(IV) with human cytochrome P450 3A4 protease.
abstract: A novel organotin DFDPT was synthesized and characterized by elemental analysis, IR, (1)H, (13)C, (119)Sn, NMR techniques,etc. In order to investigate profoundly the relationship between DFDPT with human CYP3A4 proteaset and anticancer molecular mechanism of DFDPT, the intercalative mode of binding of DFDPT with CYP3A4 under physiological conditions were comprehensively evaluated using steady state, synchronous, three-dimensional fluorescence spectroscopy,circular dichroism and molecular docking. Fluorescence emission data showed that CYP3A4 fluorescence affected by DFDPT was a static quenching procedure, which implied that DFDPT-CYP3A4 complex had been formed. Apparent binding constants Kb of CYP3A4 with compound at 298 and 310K were 2.51×10(7) and 3.09×10(5), respectively. The binding sites number n was 1.64 and 1.22, respectively. The thermodynamic parameters ΔH and ΔS of the DFDPT-CYP3A4 complex were negative, which indicated that their interaction was driven mainly by hydrogen bonding and van der Waals force. The binding of DFDPT-CYP3A4 was spontaneous process in which ΔG was negative. The synchronous results showed DFDPT induced conformational changes of CYP3A4 protein. Three-dimensional fluorescence and circular dichroism spectra results also revealed conformation of CYP3A4 protein had been possible changed in the presence of DFDPT. Molecular docking was used to study the interaction orientation between DFDPT and CYP3A4 protease. The results indicated that DFDPT interacted with a panel of amino acids in the active sites of CYP3A4 protein mainly through formation of hydrogen bond. Furthermore, the predicted binding mode of DFDPT into CYP3A4 appeared to adopt an orientation with interactions among Arg105, Ser119 and Thr309.
authors.affiliation: School of Pharmaceutical Science, Shanxi Medical University, Taiyuan 030001, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wei
authors.affiliation: School of Pharmaceutical Science, Shanxi Medical University, Taiyuan 030001, PR China.
authors.forename: Lin
authors.initials: L
authors.lastname: Niu
authors.affiliation: School of Pharmaceutical Science, Shanxi Medical University, Taiyuan 030001, PR China.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Science, Shanxi Medical University, Taiyuan 030001, PR China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Zhou
authors.affiliation: School of Pharmaceutical Science, Shanxi Medical University, Taiyuan 030001, PR China.
authors.forename: Hongzhou
authors.initials: H
authors.lastname: Dong
authors.affiliation: School of Pharmaceutical Science, Shanxi Medical University, Taiyuan 030001, PR China.
authors.forename: Depeng
authors.initials: D
authors.lastname: Kong
authors.affiliation: School of Pharmaceutical Science, Shanxi Medical University, Taiyuan 030001, PR China. Electronic address: liyunlanrr@163.com.
authors.forename: Yunlan
authors.initials: Y
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Science, Shanxi Medical University, Taiyuan 030001, PR China. Electronic address: qingshanl@yahoo.com.
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Li
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D002942:Circular Dichroism; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D009947:Organotin Compounds / Q000737:chemistry / Q000378:metabolism*; D013050:Spectrometry, Fluorescence / Q000379:methods*; D013696:Temperature
chemical_list: D000970:Antineoplastic Agents; D009947:Organotin Compounds; C000613245:bis(2,4-difluoro-N-(hydroxy-(kappa)O)benzamidato-(kappa))O)diphenyltin(IV); C063612:diphenyltin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: CYP3A4; Interaction; Molecular docking; Organotin compound; Spectroscopic study