Brown Frank K, Sherer Edward C, Johnson Scott A, Holloway M Katharine, Sherborne Bradley S
Structural Chemistry Department, MRL Research Laboratories, West Point, PA, USA.
Structural Chemistry Department, MRL Research Laboratories, Rahway, NJ, USA.
J Comput Aided Mol Des. 2017 Mar;31(3):255-266. doi: 10.1007/s10822-016-9993-1. Epub 2016 Nov 23.
On October 5, 1981, Fortune magazine published a cover article entitled the "Next Industrial Revolution: Designing Drugs by Computer at Merck". With a 40+ year investment, we have been in the drug design business longer than most. During its history, the Merck drug design group has had several names, but it has always been in the "design" business, with the ultimate goal to provide an actionable hypothesis that could be tested experimentally. Often the result was a small molecule but it could just as easily be a peptide, biologic, predictive model, reaction, process, etc. To this end, the concept of design is now front and center in all aspects of discovery, safety assessment and early clinical development. At present, the Merck design group includes computational chemistry, protein structure determination, and cheminformatics. By bringing these groups together under one umbrella, we were able to align activities and capabilities across multiple research sites and departments. This alignment from 2010 to 2016 resulted in an 80% expansion in the size of the department, reflecting the increase in impact due to a significant emphasis across the organization to "design first" along the entire drug discovery path from lead identification (LID) to first in human (FIH) dosing. One of the major advantages of this alignment has been the ability to access all of the data and create an adaptive approach to the overall LID to FIH pathway for any modality, significantly increasing the quality of candidates and their probability of success. In this perspective, we will discuss how we crafted a new strategy, defined the appropriate phenotype for group members, developed the right skillsets, and identified metrics for success in order to drive continuous improvement. We will not focus on the tactical implementation, only giving specific examples as appropriate.
1981年10月5日，《财富》杂志发表了一篇封面文章，题为《下一次工业革命：默克公司的计算机药物设计》。经过40多年的投入，我们从事药物设计业务的时间比大多数公司都要长。在其历史上，默克药物设计团队有过几个名字，但一直从事“设计”业务，最终目标是提供一个可通过实验进行测试的可行假设。通常结果是一个小分子，但也可能同样容易地是一种肽、生物制品、预测模型、反应、过程等。为此，设计概念现在在发现、安全性评估和早期临床开发的各个方面都处于前沿和中心位置。目前，默克设计团队包括计算化学、蛋白质结构测定和化学信息学。通过将这些团队整合在一个框架下，我们能够协调多个研究地点和部门的活动及能力。2010年至2016年的这种协调导致该部门规模扩大了80%，这反映出由于整个组织在从先导化合物识别（LID）到首次人体给药（FIH）的整个药物发现过程中大力强调“先设计”，影响力有所增加。这种协调的一个主要优势是能够获取所有数据，并针对任何模式的从LID到FIH的整个路径创建一种适应性方法，显著提高了候选药物的质量及其成功的概率。在这篇观点文章中，我们将讨论我们如何制定新战略、为团队成员定义合适的表型、培养正确的技能组合以及确定成功的指标，以推动持续改进。我们不会专注于战术实施，仅在适当的时候给出具体例子。
