NEW METHOD TO CALCULATE BINDING FREE ENERGY

计算化学和分子模拟是必不可少的 现代药物设计过程的一部分。然而，目前， 分子建模方法只能提供相当定性的 关于不同化合物对给定目标的亲和力的信息 地点。目前解决这类问题的唯一严格方法是 自由能微扰(FEP)技术或多或少受到限制 到“小扰动”。然而，在实践中的药物设计往往 与相对较大的抑制剂进行交易，这些抑制剂与 相互作用，使得相对或绝对自由能都不能 用FEP/MD方法在合理的计算时间内得到。 这种两难境地导致Aqvist等人设计了一种简化的方法 不涉及“突变路径”，这主要是阻碍 FEP方法。我们遵循了Aqvist的想法，正在努力开发 它。我们发现Aqvist方法中的一个参数依赖于 目标站点的性质。几个蛋白质/配体系统 经验算，计算结果与实测值基本吻合。 实验数据令人振奋。

Computational chemistry and molecular modeling are an essential part of the modern drug design process. At present, however, molecular modeling methods can only provide rather qualitative information on the affinity of different compounds for a given target site. The only rigorous approach to this type of problem today is the free energy perturbation (FEP) technique which is more or less limited to "small perturbations". Drug design in practice, however, often deals with relatively large inhibitors that differ considerably from each other so that neither relative nor absolute free energies can be obtained with the FEP/MD method within reasonable computing time. This dilemma led Aqvist et al to devise a simplified approach that does not involve the "mutational paths" which are mainly what hampers the FEP methods. We followed Aqvist's idea and are trying to develop it. We found that one parameter in the Aqvist method depends on the nature of the target site. Several protein/ligand systems were checked and the calculated results are in reasonable agreement with the experimental data which is very encouraging.