Makara G M, Keserû G M
Department of Molecular Biology and Pharmacology, Washington University at St. Louis, Missouri 63110, USA.
J Med Chem. 1997 Dec 5;40(25):4154-9. doi: 10.1021/jm970129s.
Tiazofurin, an important inhibitor of inosine 5'-monophosphate dehydrogenase, has been argued to possess a restricted glycosylic bond due to an energetically favorable intramolecular (1-4) electrostatic interaction between the partial positive sulfur and the negative oxygen of the ribose. This rigidity has been appointed as a plausible cause that leads to activity in the sulfur containing compounds as opposed to the inactive oxazofurin-like analogues (i.e. S is replaced by an oxygen) that lack this favorable interaction. We reinvestigated this notion by using computational methods to report that although the above interaction (or its lack) is likely to contribute to the low-energy conformation of these classes of molecules, the flexibility of the glycosylic bond is ultimately determined by steric interaction of the heteroatoms with the C2'-H and O4' of the ribose. Application of this theory in the design of new analogues is presented as well.
硫唑嘌呤是肌苷5'-单磷酸脱氢酶的重要抑制剂，由于核糖的部分正电荷硫与负电荷氧之间存在能量上有利的分子内（1-4）静电相互作用，有人认为它具有受限的糖苷键。这种刚性被认为是导致含硫化合物具有活性的一个合理原因，与之形成对比的是缺乏这种有利相互作用的无活性恶唑嘌呤类似物（即硫被氧取代）。我们通过计算方法重新研究了这一观点，结果表明，尽管上述相互作用（或其缺乏）可能有助于这些类分子的低能构象，但糖苷键的灵活性最终由杂原子与核糖的C2'-H和O4'的空间相互作用决定。本文还介绍了该理论在新类似物设计中的应用。
