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Halogen bonding for the design of inhibitors by targeting the S1 pocket of serine proteases

机译：通过靶向丝氨酸蛋白酶的S1口袋来设计抑制剂的卤素键

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Halogen bonding (or X bonding) has attracted increasing interest due to its significant role in molecular recognition in biological systems. Trypsin-like serine proteases have many physiological and pathophysiological functions. There is therefore extensive interest in generating specific inhibitors for pharmacological intervention in their enzymatic activity. We study here if it is possible to use halogenated compounds as the P1 group to bind to the S1 specificity pocket of trypsin-like serine proteases to avoid the low bioavailability of the amidine or guanidine P1 group that is typically used in many inhibitors. We used 4-chlorobenzylamine (ClBA), 4-bromobenzylamine (BrBA) and 4-iodobenzylamine (IBA) as probes to test their binding modes to a trypsin-like serine protease, urokinase-type plasminogen activator (uPA), which has been recognized as a marker for breast cancer and an important target for inhibitor development. The results showed that these compounds inhibited uPA with stronger efficacies compared with their non-halogenated analogues. We also determined the high-resolution crystal structures of uPA in complex with BrBA and IBA, respectively. The structures revealed that BrBA bound to the S1 pocket of uPA via halogen bonds, but IBA did not make halogen bonds with uPA, demonstrating that the iodine may not be the best choice as a target moiety for serine proteases. These results advocate halogen bonding, especially bromine bonding, as an efficient strategy for the future design of novel inhibitors against trypsin-like serine proteases to provide strong potency and promote bioavailability.
机译：由于卤素键（或X键）在生物系统中的分子识别中起着重要作用，因此引起了越来越多的关注。胰蛋白酶样丝氨酸蛋白酶具有许多生理和病理生理功能。因此，引起广泛关注的是产生用于其酶活性的药理学干预的特异性抑制剂。我们在这里研究是否有可能使用卤代化合物作为P1基团与胰蛋白酶样丝氨酸蛋白酶的S1特异性口袋结合，以避免通常在许多抑制剂中使用的am或胍基P1基团的低生物利用度。我们使用4-氯苄胺（ClBA），4-溴苄胺（BrBA）和4-碘苄胺（IBA）作为探针来测试其与胰蛋白酶样丝氨酸蛋白酶，尿激酶型纤溶酶原激活剂（uPA）的结合模式作为乳腺癌的标志物和抑制剂开发的重要目标。结果表明，与非卤代类似物相比，这些化合物对uPA的抑制作用更强。我们还确定了分别与BrBA和IBA配合的uPA的高分辨率晶体结构。该结构表明，BrBA通过卤素键与uPA的S1口袋结合，但IBA并未与uPA形成卤素键，这表明碘可能不是丝氨酸蛋白酶靶点的最佳选择。这些结果提倡卤素键，尤其是溴键，作为未来设计针对胰蛋白酶样丝氨酸蛋白酶的新型抑制剂的有效策略，以提供强大的功效并促进生物利用度。

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