Chakraborty Hirak, Sarkar Munna
Chemical Sciences Division, Saha Institute of Nuclear Physics, 1/AF, Bidhannagar, Calcutta-700 064, India.
Biophys Chem. 2005 Aug 22;117(1):79-85. doi: 10.1016/j.bpc.2005.04.016.
Molecules, whose pK(a) values can be easily fine-tuned by their microenvironment, are expected to be profoundly affected by the heterogeneous environments of membranes. Membrane parameters can have a strong effect in choosing a particular structural form of a molecule for incorporation/interaction. A case study has been presented for piroxicam, a non-steroidal anti-inflammatory drug of oxicam group, whose targets are cyclooxygenases, which are membrane active proteins. The structural dynamism of piroxicam is reflected in the ease with which it can switchover or convert from one prototropic form to the other guided by its environment. In this work we have studied the effect of varying hydrophobic chain length and surface charges in fine-tuning the interaction of piroxicam with micelles. Interaction of piroxicam with three types of micelles with identical negatively charged head groups and varying tail lengths viz., sodium dodecyl sulfate (S12S), sodium decyl sulfate (S10S) and sodium octyl sulfate (S8S) shows that there is a shift in the apparent pK(a) in the direction that favors the switchover or conversion from the anionic form to the global neutral form. The binding constants of piroxicam with three micelles show a linear dependence on chain length. Interaction was also studied with micelles having oppositely charged head groups and different chain lengths viz., dodecyl N,N,N-trimethyl ammonium bromide (DTAB) and cetyl N,N,N-trimethyl ammonium bromide (CTAB). For micelles having identical chain lengths but oppositely charged head groups viz., S12S and DTAB, pK(a) shifts in two opposite directions compared to that in the absence of any surfactant. This is expected when electrostatic force is the only driving force. This case study demonstrates the effect of hydrophobic chain length and surface charges in fine-tuning the equilibrium between different structural forms of piroxicam. Our results also imply that for structurally dynamic drugs like piroxicam the nature of the biomembranes, characterized by different membrane parameters, should play a crucial role in choosing a particular structural form of the drug that will be finally presented to their targets.
其pK(a)值可通过微环境轻松微调的分子，预计会受到膜的异质环境的深刻影响。膜参数在选择用于掺入/相互作用的特定分子结构形式时可能具有强烈影响。已针对吡罗昔康进行了案例研究，吡罗昔康是昔康类非甾体抗炎药，其靶点是环氧化酶，而环氧化酶是膜活性蛋白。吡罗昔康的结构动态性体现在它能够在其环境的引导下轻松地从一种质子异构形式转换为另一种形式。在这项工作中，我们研究了改变疏水链长度和表面电荷对微调吡罗昔康与胶束相互作用的影响。吡罗昔康与三种具有相同带负电头部基团和不同尾链长度的胶束，即十二烷基硫酸钠（S12S）、癸基硫酸钠（S10S）和辛基硫酸钠（S8S）的相互作用表明，表观pK(a)向有利于从阴离子形式转换为整体中性形式的方向发生了偏移。吡罗昔康与三种胶束的结合常数显示出对链长度的线性依赖性。还研究了与具有相反电荷头部基团和不同链长度的胶束，即十二烷基三甲基溴化铵（DTAB）和十六烷基三甲基溴化铵（CTAB）的相互作用。对于具有相同链长度但相反电荷头部基团的胶束，即S12S和DTAB，与不存在任何表面活性剂时相比，pK(a)向两个相反方向偏移。当静电力是唯一驱动力时，这是可以预期的。该案例研究证明了疏水链长度和表面电荷在微调吡罗昔康不同结构形式之间平衡方面所起的作用。我们的结果还意味着，对于像吡罗昔康这样结构动态的药物，以不同膜参数为特征的生物膜的性质，在选择最终呈现给其靶点的特定药物结构形式时应发挥关键作用。
