Lee Chul-Jin, Liang Xiaofei, Wu Qinglin, Najeeb Javaria, Zhao Jinshi, Gopalaswamy Ramesh, Titecat Marie, Sebbane Florent, Lemaitre Nadine, Toone Eric J, Zhou Pei
Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA.
Department of Chemistry, Duke University, Durham, North Carolina 27708, USA.
Nat Commun. 2016 Feb 25;7:10638. doi: 10.1038/ncomms10638.
Conformational dynamics plays an important role in enzyme catalysis, allosteric regulation of protein functions and assembly of macromolecular complexes. Despite these well-established roles, such information has yet to be exploited for drug design. Here we show by nuclear magnetic resonance spectroscopy that inhibitors of LpxC--an essential enzyme of the lipid A biosynthetic pathway in Gram-negative bacteria and a validated novel antibiotic target--access alternative, minor population states in solution in addition to the ligand conformation observed in crystal structures. These conformations collectively delineate an inhibitor envelope that is invisible to crystallography, but is dynamically accessible by small molecules in solution. Drug design exploiting such a hidden inhibitor envelope has led to the development of potent antibiotics with inhibition constants in the single-digit picomolar range. The principle of the cryptic inhibitor envelope approach may be broadly applicable to other lead optimization campaigns to yield improved therapeutics.
构象动力学在酶催化、蛋白质功能的变构调节以及大分子复合物的组装中起着重要作用。尽管有这些已确立的作用，但此类信息尚未用于药物设计。在这里，我们通过核磁共振光谱表明，LpxC抑制剂——革兰氏阴性菌脂质A生物合成途径中的一种必需酶，也是一个经过验证的新型抗生素靶点——除了在晶体结构中观察到的配体构象外，还能进入溶液中的其他次要构象状态。这些构象共同描绘出一个晶体学无法看到的抑制剂包络，但小分子在溶液中可以动态地接近它。利用这种隐藏的抑制剂包络进行药物设计已导致开发出抑制常数在个位数皮摩尔范围内的强效抗生素。隐蔽抑制剂包络方法的原理可能广泛适用于其他先导优化活动，以产生改进的治疗药物。
