The interference of human heat shock protein 90 (HSP90) in many signalling networks associated with cancer progression makes it an important drug target. In the present work, we investigated the binding ability of 9 s...The interference of human heat shock protein 90 (HSP90) in many signalling networks associated with cancer progression makes it an important drug target. In the present work, we investigated the binding ability of 9 selenoderivatives of geldanamycin (GMDSe) at the N-terminal domain of HSP90 derived from Protein Data Bank (PDB code: 1YET) based on ligand-protein docking. All selenoderivatives interacted positively with HSP90, yet the binding strength decreased when replacing monovalent oxygen in position 1 (GMDSe1) or 9 (GMDSe9). Hydrogen-bonding and lipophilic interactions between selenoderivatives and amino acid residues in the inhibitor site of HSP90 were thermodynamically the main forces driving the binding stability. Molecular electrostatic potential surfaces of the selenoderivatives showed marked non polar areas, which were probably involved in the lipophilic interactions with the hydrophobic residues of amino acids. Interestingly, the amino acid residues forming the hydrogen bonds with GMD were also involved in the hydrogen-bonding interactions with the selenoderivatives. Moreover, HSP90 interacted with the GMDSe6 and GMDSe7 selenoderivatives stronger than with GMD, while maintaining lipophilic interactions and hydrogen bonds with amino acid residues like Asp93, which are catalytically crucial for therapeutic properties of HSP90 inhibitors. This finding should guide further studies of pharmacophore properties of GMD selenoderivatives in order to explore their therapeutic properties. It is noteworthy that selenium has been suggested to reduce the risk of various types of cancers.展开更多
Inactivation of Glucokinase (GK) is associated with diabetes. Therefore, design of drugs targeting the GK activator site is currently integrated in the?strategy of the diabetes treatment.?The present work investigated...Inactivation of Glucokinase (GK) is associated with diabetes. Therefore, design of drugs targeting the GK activator site is currently integrated in the?strategy of the diabetes treatment.?The present work investigated the affinity of 30 ligands to GK based on molecular docking using the Gold 5.6 program. Glucokinase’s structure was derived from the Protein Data Bank (PDB Code?3S41), while the ligands were seleno, sulfo and oxo derivatives of the co-crystallized?carboxamide activator (PDB code:?S41). The results of the ligand-protein docking?revealed that GK formed thermodynamically stable complexes with all ligands. The main forces stabilizing the complexes are lipophilic interactions, enhanced by hydrogen bonds. Ligand molecular areas responsible for lipophilic and hydrogen bonding contacts with amino acid residues in the allosteric site of GK were evidenced by molecular electrostatic potentials (MEPs). Interestingly,?twelve of the S41 derivatives interacted with GK more strongly than the co-crystallized activator, while maintaining the lipophilic contacts with key amino acid residues like Arg63, which are catalytically crucial for?therapeutic properties of GK activators (GKAs).?It is noteworthy that divalent Se and S atoms were also involved in chalcogen bonds in the GKA site. Those bonds were nearly linear like hydrogen bonds. Such bond directionality should guide the design of pharmacophoric ligands containing chalcogen atoms.展开更多
Iron(III)-5,10,15,20-tetrakis(4-sulfonatophenyl) porphyrin (FeTPPS) is used as non-physiological metalloporphyrin model for the natural iron (III)-protoporphyrin IX (FePPIX) resulting from hemoglobin degradation to in...Iron(III)-5,10,15,20-tetrakis(4-sulfonatophenyl) porphyrin (FeTPPS) is used as non-physiological metalloporphyrin model for the natural iron (III)-protoporphyrin IX (FePPIX) resulting from hemoglobin degradation to investigate ligand binding reactions in aqueous solution. Studies were conducted on the interaction of FeTPPS with Chloroquine, Quinine, and Quinidine, which are historically the most common quinoline-based drugs used to treat malaria, an infectious disease afflicting several hundred millions every year worldwide, mainly in tropical regions. Using UV-Visible spectrophotometry, the binding reaction was studied at pH 7.40 in purely aqueous solution, and in aqueous solution containing NaNO3 at concentration of 0.1 M. Fitted titration curves obtained were in agreement with experimental data according to a formation scheme of 1:1 complex (1 FeTPPS μ-oxo-dimer: 1 Antimalarial). Values of apparent binding constant (K) obtained were between 4.3 × 103 M-1 to 7.59 × 104 M-1, demonstrating that FeTPPS and the antimalarials formed stable complexes. The stability of the complex decreased when NaNO3 was added to the solution. This ionic strength dependence was ascribed to electrostatic effects. Quinine and Chloroquine interacted with FeTPPS stronger than Quinidine did. Chloroquine showed the strongest affinity to FeTPPS. These findings revealed the influence of steric and stereochemical factors. Molecular electrostatic potentials (MEP) calculated with Hartree-Fock theory argue in favor of π-π and electrostatic interactions between reaction partners as driving forces for the complex formation. In the case of FeTPPS: Chloroquine interaction, it is suggested that an intramolecular hydrogen bond is formed between phenyl??and quinuclidine N-H+ as additional force stabilizing the complex. Analysis of crystallographic data using the Cambridge Structural Database (CSD) gave evidence of the hydrogen bond formation between phenyl??and N-H+ groups in 370 structures.展开更多
文摘马来酸氯苯那敏(chlorpheniramine maleate,CPM),化学名为2-[对-氯-α-(二甲氨基)乙基丁苯基],又名扑尔敏,分子式C20H23ClN2O4,本文采用密度泛函理论(density functional theory,DFT),在M06-2X/6-311+g(d,p)水平上对扑尔敏分子的两种可能的结构进行了优化,优化结果显示分子基态结构具有C1对称性,分子由50个原子组成,共有144个简正自由度,所有的简正振动模式均具有拉曼活性.计算结果表明,吡啶环和苯环所在平面的二面角是92.1°,丁烯二酸和苯环所在平面的二面角是-174.5°.O40-H41和H41-N25键长分别为0.103 nm、0.162 nm,O40-H41-N25键角为175.29°,采用多功能波函数Multiwfn软件处理结果表明用于表征氢键强度的CVB指数(CVB指数越负,通常氢键越强.)为-0.2268,结果表明O40-H41-N25原子之间存在氢键,马来酸通过羧基上的氢原子和氯苯那敏吡啶环上的N原子通过氢键作用相结合;通过频率计算,获得了扑尔敏分子的拉曼光谱,并利用势能函数分布(PED)对拉曼光谱进行了指认,对谱图信息比较丰富的200-1800 cm-1波段进行了分析归属;此外分析并讨论了扑尔敏分子的前线轨道,扑尔敏分子的最高占据轨道HOMO和最低未占据分子轨道LUMO轨道能量分别为-7.95 e V、-1.05 e V,能级差为6.90 e V.为扑尔敏分子的光谱测定和电子结构分析提供了理论基础.
文摘The interference of human heat shock protein 90 (HSP90) in many signalling networks associated with cancer progression makes it an important drug target. In the present work, we investigated the binding ability of 9 selenoderivatives of geldanamycin (GMDSe) at the N-terminal domain of HSP90 derived from Protein Data Bank (PDB code: 1YET) based on ligand-protein docking. All selenoderivatives interacted positively with HSP90, yet the binding strength decreased when replacing monovalent oxygen in position 1 (GMDSe1) or 9 (GMDSe9). Hydrogen-bonding and lipophilic interactions between selenoderivatives and amino acid residues in the inhibitor site of HSP90 were thermodynamically the main forces driving the binding stability. Molecular electrostatic potential surfaces of the selenoderivatives showed marked non polar areas, which were probably involved in the lipophilic interactions with the hydrophobic residues of amino acids. Interestingly, the amino acid residues forming the hydrogen bonds with GMD were also involved in the hydrogen-bonding interactions with the selenoderivatives. Moreover, HSP90 interacted with the GMDSe6 and GMDSe7 selenoderivatives stronger than with GMD, while maintaining lipophilic interactions and hydrogen bonds with amino acid residues like Asp93, which are catalytically crucial for therapeutic properties of HSP90 inhibitors. This finding should guide further studies of pharmacophore properties of GMD selenoderivatives in order to explore their therapeutic properties. It is noteworthy that selenium has been suggested to reduce the risk of various types of cancers.
文摘Inactivation of Glucokinase (GK) is associated with diabetes. Therefore, design of drugs targeting the GK activator site is currently integrated in the?strategy of the diabetes treatment.?The present work investigated the affinity of 30 ligands to GK based on molecular docking using the Gold 5.6 program. Glucokinase’s structure was derived from the Protein Data Bank (PDB Code?3S41), while the ligands were seleno, sulfo and oxo derivatives of the co-crystallized?carboxamide activator (PDB code:?S41). The results of the ligand-protein docking?revealed that GK formed thermodynamically stable complexes with all ligands. The main forces stabilizing the complexes are lipophilic interactions, enhanced by hydrogen bonds. Ligand molecular areas responsible for lipophilic and hydrogen bonding contacts with amino acid residues in the allosteric site of GK were evidenced by molecular electrostatic potentials (MEPs). Interestingly,?twelve of the S41 derivatives interacted with GK more strongly than the co-crystallized activator, while maintaining the lipophilic contacts with key amino acid residues like Arg63, which are catalytically crucial for?therapeutic properties of GK activators (GKAs).?It is noteworthy that divalent Se and S atoms were also involved in chalcogen bonds in the GKA site. Those bonds were nearly linear like hydrogen bonds. Such bond directionality should guide the design of pharmacophoric ligands containing chalcogen atoms.
文摘Iron(III)-5,10,15,20-tetrakis(4-sulfonatophenyl) porphyrin (FeTPPS) is used as non-physiological metalloporphyrin model for the natural iron (III)-protoporphyrin IX (FePPIX) resulting from hemoglobin degradation to investigate ligand binding reactions in aqueous solution. Studies were conducted on the interaction of FeTPPS with Chloroquine, Quinine, and Quinidine, which are historically the most common quinoline-based drugs used to treat malaria, an infectious disease afflicting several hundred millions every year worldwide, mainly in tropical regions. Using UV-Visible spectrophotometry, the binding reaction was studied at pH 7.40 in purely aqueous solution, and in aqueous solution containing NaNO3 at concentration of 0.1 M. Fitted titration curves obtained were in agreement with experimental data according to a formation scheme of 1:1 complex (1 FeTPPS μ-oxo-dimer: 1 Antimalarial). Values of apparent binding constant (K) obtained were between 4.3 × 103 M-1 to 7.59 × 104 M-1, demonstrating that FeTPPS and the antimalarials formed stable complexes. The stability of the complex decreased when NaNO3 was added to the solution. This ionic strength dependence was ascribed to electrostatic effects. Quinine and Chloroquine interacted with FeTPPS stronger than Quinidine did. Chloroquine showed the strongest affinity to FeTPPS. These findings revealed the influence of steric and stereochemical factors. Molecular electrostatic potentials (MEP) calculated with Hartree-Fock theory argue in favor of π-π and electrostatic interactions between reaction partners as driving forces for the complex formation. In the case of FeTPPS: Chloroquine interaction, it is suggested that an intramolecular hydrogen bond is formed between phenyl??and quinuclidine N-H+ as additional force stabilizing the complex. Analysis of crystallographic data using the Cambridge Structural Database (CSD) gave evidence of the hydrogen bond formation between phenyl??and N-H+ groups in 370 structures.
