Efficient and Accurate Force Fields for Computer-Aided Drug Design

用于计算机辅助药物设计的高效精确力场 计算机辅助药物设计受到描述药物的力场的有限精度的阻碍。 药物分子、其靶标和共享环境之间的相互作用。自动化协议，自适应 力匹配（AFM），提出了创建定制的力场，使更有效和准确的 候选药物结构和功能的计算研究。实施AFM将需要 采用高效技术进行构型取样和量子力学计算 大型系统。将在一系列日益复杂的目标中制定和评价这一方法。在 前两个目标是生成力场，用于预测小分子类药物的水合自由能， 分子和宾主对的结合亲和力。该方法的性能将在 最近的SAMPL4竞赛的例子。在最后一个目标中，为模拟创建力场， 允许鉴定在生理pH下具有改善的溶解度和稳定性的乳链菌肽衍生物， 基于乳链菌肽的新型抗生素的设计。这类药物通常被称为硫醚抗生素，它 有望解决日益严重的多重耐药细菌感染问题。

Efficient and Accurate Force Fields for Computer-Aided-Drug Design Computer-aided drug design is hampered by the limited accuracy in the force fields that describe the interactions between drug molecules, their targets, and shared environment. An automated protocol, adaptive force matching (AFM), is proposed for creating customized force fields that enable more efficient and accurate computational studies of the structure and function of drug candidates. Putting AFM in place will require the adaption of highly efficient techniques for sampling of configurations and quantum mechanical calculations of large systems. The approach will be developed and evaluated in a series of aims with increasing complexity. In the first two aims, force fields are generated for prediction of hydration free energies of small drug-like molecules and of the binding affinities for guest-host pairs. The performance of the method will be tested on examples from the recent SAMPL4 competition. In the last aim, force fields are created for simulations that allow one to identify nisin derivatives with improved solubility and stability at physiological pH as required for the design of nisin-based novel antibiotics. This class of drug is generally referred to as lantibiotics, and it carries the promise to address the increasingly severe problem of multi-drug resistant bacterial infection.