NEW METHOD TO CALCULATE BINDING FREE ENERGY

计算化学和分子建模是一个必不可少的 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 不同化合物对给定靶标的亲和力信息 绝佳的价钱 今天解决这类问题的唯一严格方法是 自由能微扰（FEP）技术，其或多或少受到限制 “小扰动”。 然而，药物设计在实践中往往 涉及相对较大的抑制剂， 因此，无论是相对自由能还是绝对自由能， 在合理的计算时间内使用FEP/MD方法获得。 这种两难境地促使Aqvist等人设计了一种简化的方法， 不涉及“突变路径”，这主要是什么阻碍 FEP方法。 我们遵循阿奎斯特的想法， 了 我们发现Aqvist方法中的一个参数取决于 目标地点的性质。 几种蛋白质/配体系统， 经检验，计算结果与 实验数据非常令人鼓舞。

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.