Bachhawat K, Thomas C J, Surolia N, Surolia A
Molecular Biophysics Unit, Indian Institute of Science, Bangalore-, 560012, India.
Biochem Biophys Res Commun. 2000 Oct 5;276(3):1075-9. doi: 10.1006/bbrc.2000.3592.
Quinoline-containing drugs such as chloroquine and quinine have had a long and successful history in antimalarial chemotherapy. Identification of ferriprotoporphyrin IX ([Fe(III)PPIX], haematin) as the drug receptors for these antimalarials called for investigations of the binding affinity, mode of interaction, and the conditions affecting the interaction. The parameters obtained are significant in recent times with the emergence of chloroquine resistant strains of the malaria parasites. This has underlined the need to unravel the molecular mechanism of their action so as to meet the requirement of an alternative to the existing antimalarial drugs. The isothermal titration calorimetric studies on the interaction of chloroquine with haematin lead us to propose an altered mode of binding. The initial recognition is ionic in nature mediated by the propionyl group of haematin with the quaternary nitrogen on CQ. This ionic interaction induces a conformational change, such as to favour binding of subsequent CQ molecules. On the contrary, conditions emulating the cytosolic environment (pH 7.4 and 150 mM salt) reveal the hydrophobic force to be the sole contributor driving the interaction. Interaction of a carefully selected panel of quinoline antimalarial drugs with monomeric ferriprotoporphyrin IX has also been investigated at pH 5.6 mimicking the acidic environment prevalent in the food vacuoles of parasite, the center of drug activity, which are consistent with their antimalarial activity.
含喹啉的药物，如氯喹和奎宁，在抗疟化疗方面有着悠久且成功的历史。铁原卟啉IX（[Fe(III)PPIX]，血红素）被确定为这些抗疟药物的受体，这就需要对其结合亲和力、相互作用模式以及影响相互作用的条件进行研究。随着疟原虫氯喹耐药菌株的出现，近年来所获得的这些参数具有重要意义。这突出表明有必要阐明其作用的分子机制，以满足寻找现有抗疟药物替代品的需求。对氯喹与血红素相互作用的等温滴定量热研究使我们提出了一种改变的结合模式。最初的识别本质上是离子性的，由血红素的丙酰基与氯喹上的季铵氮介导。这种离子相互作用会引起构象变化，从而有利于后续氯喹分子的结合。相反，模拟胞质环境（pH 7.4和150 mM盐）的条件表明，疏水力是驱动相互作用的唯一因素。在pH 5.6模拟寄生虫食物泡中普遍存在的酸性环境（药物活性中心）下，还研究了一组精心挑选的喹啉抗疟药物与单体铁原卟啉IX的相互作用，这与它们的抗疟活性是一致的。
