I decided to weigh in on the ongoing discussion about medicinal chemistry education and training with my thoughts on the matter, as I began my career in industry (Parke-Davis, Eli Lilly and Merck) and later moved into academia (Vanderbilt University/Warren Center for Neuroscience Drug Discovery). First and foremost, training in synthetic organic chemistry is essential. A deep understanding of mechanistic organic chemistry and exposure to a wide breadth of synthetic chemistry is key not only to be able to handle any chemistry that may come your way but also to understand reasonable biotransformations in metabolism. Medicinal chemistry trainees (graduate students and postdocs) should have a side project in synthesis or methodology to complement their med chem projects. Seek broad drug discovery knowledge. I have always made it a point to talk routinely with the lead pharmacologist/biochemists and really understand the assays that were being run (primary, secondary and tertiary). Similarly, learning drug metabolism and pharmacokinetics (DMPK) on the fly can be challenging, but weekly conversations with the DMPK lead for your programs can be incredibly insightful and quickly increases your depth of understanding of both in vitro and in vivo DMPK. If you do not understand what the DMPK data is informing you of, how can you design balanced compounds? Strive to deeply understand the pharmacodynamic assays that are being performed─learn caveats between mouse and rat models and species-specific sensitivities to the molecular mechanism you are working on. It really boils down to communication. Talk. Ask questions. Read─not only the Journal of Medicinal Chemistry and organic chemistry journals but also pharmacology, biochemistry and DMPK journals. Discuss what you have read with your colleagues to appreciate a deeper level of understanding. As the Harvard chemist Frank Westheimer is quoted, “A couple of months in the laboratory can frequently save a couple of hours in the library.” With journals online and so much content readily available at your computer, it is so easy to spend a little time reading to save hours in the lab. The goal of every medicinal chemist should be to evolve into a well-rounded, holistic drug discovery scientist. The most successful medicinal chemists in both industry and academia have a deep understanding and appreciation for pharmacology/biochemistry, DMPK and the entire drug discovery process. Attend conferences─present posters and speak. Publish. Oral and written communications cement your place in the scientific community and establish you as a leader in the medicinal chemistry and drug discovery fields. You also hone your craft and become a better scientist. Every June, Drew University’s “Residential School on Medicinal Chemistry and Biology in Drug Discovery (ResMed)” is taught by thought leaders in medicinal chemistry, pharmacology, DMPK and translational sciences (ResMed: Medicinal Chemistry and Biology in Drug Discovery). This is a terrific primer for early-stage medicinal chemists in both industry and academia, an immersive experience for learning all the critical concepts as well as seeing them applied to case studies. You also make great connections at schools such as this. Engage in target meetings─prepare in advance and push the boundaries. Don’t over-design/over-engineer every target compound─do not talk yourself out of a compound synthesis─test the model with empirical data. Always allow for some “crazy” ideas to push new frontiers and allow for serendipity─many program breakthroughs occur this way. Ensure an idea is fully tested─consider small, focused libraries to truly cover chemical space to vet a concept. Do not over-rely on models─they are models of a static ligand–receptor complex that may or may not be physiologically relevant. I often see talks where ideas were disregarded because they did not fit with the model. Vet and validate your models with empirical data. Structure-based design can be amazing for certain targets and a quagmire of grief for others. Balance. The same holds true for machine learning and AI outputs that are only as good as the training sets for the algorithms. Tremendous promise is available here if deep training data sets are available. In my experience, there are no general panaceas─it is all about the right tool for the right project at the right time. Beware of the cure-all magic elixirs and being limited by a platform technology─balanced tools, strategies and approaches win the day. Create a balanced toolbox and implement judiciously. Of greatest importance: Do not focus on compound potency alone─potency is seductive and easy to engineer with lipophilicity, but often at the cost of drug-like properties. Do not kick a solubility problem “down the road” into development─development will stall and costs escalate. Balanced ligands are the ones that make it into the clinic. Building in solubility and unbound fractions can provide a ligand with excellent pharmacodynamic efficacy, despite lower potency. Focus on physicochemical properties─even when you see erosion of potency─it will be OK. Drug discovery is all about balance─do not hyperfocus on potency or any single parameter. Finally, I would say the best advice for a medicinal chemist is to do your absolute best to design studies/assays to kill your compound, to kill the series, and to kill the target/program. If you are not able to do so, then you have a compound and a program that may move smoothly through development. Again, I evoke the concept of balance. Balance being a champion for your program─that is essential─but balance that championing with a desire to not just meet a candidate delivery metric but to also kill inferior compounds/programs to ensure you survive development and enter the clinic. If possible, be on the early development team and follow the IND-enabling studies, as you will learn a great deal from all the CMC (chemistry, manufacturing and controls), formulation and toxicology work. Join ACS MEDI, the ACS Division of Medicinal Chemistry (https://www.acsmedchem.org/). Volunteer. Get involved. Be a part of a large and vibrant community of medicinal chemists and drug hunters. Join a committee and help plan session for the MEDI talks at the ACS National Meetings. Being engaged is a great way to grow in the field. When you first begin your career, seek an experienced mentor─knowledge from practical drug discovery is so essential and cannot be found in a textbook; however, key lessons/solutions are found in journals─READ! Once you become established and a leader in your own right, mentor others. Pass knowledge down. Never stop learning─read daily. The world needs new medicines─the world need medicinal chemists─the world needs you. This article has not yet been cited by other publications.

中文翻译：

---

药物化学教育与培训


我决定用我的想法来权衡正在进行的关于药物化学教育和培训的讨论，因为我开始了我的工业职业生涯（Parke-Davis、Eli Lilly 和 Merck），后来进入了学术界（范德堡大学/沃伦神经科学药物发现中心）。首先，合成有机化学的培训是必不可少的。对机理有机化学的深刻理解和广泛的合成化学知识不仅是能够处理任何可能遇到的化学反应的关键，也是理解新陈代谢中合理的生物转化的关键。药物化学实习生（研究生和博士后）应该有一个合成或方法方面的业余项目，以补充他们的医学化学项目。寻求广泛的药物发现知识。我一直强调定期与首席药理学家/生物化学家交谈，并真正了解正在进行的分析（一级、二级和三级）。同样，即时学习药物代谢和药代动力学 （DMPK） 可能具有挑战性，但每周与您的项目的 DMPK 负责人的对话可能会非常有洞察力，并迅速增加您对体外和体内 DMPK 的理解深度。如果您不了解 DMPK 数据提供的信息，您如何设计平衡化合物？努力深入了解正在进行的药效学分析——了解小鼠和大鼠模型之间的注意事项以及物种特异性对您正在研究的分子机制的敏感性。这真的归结为沟通。说话。提问。不仅阅读 Journal of Medicinal Chemistry 和有机化学期刊，还阅读 Pharmacology、biochemistry 和 DMPK 期刊。 与同事讨论您阅读的内容，以欣赏更深层次的理解。正如哈佛大学化学家 Frank Westheimer 所说，“在实验室里呆上几个月，通常可以节省几个小时在图书馆里的时间。有了在线期刊和计算机上随时可用的大量内容，花一点时间阅读以节省实验室时间非常容易。每个药物化学家的目标都应该是发展成为全面、全面的药物发现科学家。工业界和学术界最成功的药物化学家对药理学/生物化学、DMPK 和整个药物发现过程都有深刻的理解和欣赏。参加会议 ─ 展示海报和演讲。发布。口头和书面交流巩固了您在科学界的地位，并确立了您作为药物化学和药物发现领域领导者的地位。你也会磨练自己的手艺，成为一名更好的科学家。每年 6 月，德鲁大学的“药物发现中的药物化学和生物学寄宿学校 （ResMed）”由药物化学、药理学、DMPK 和转化科学的思想领袖授课（ResMed：药物发现中的药物化学和生物学）。对于工业界和学术界的早期药物化学家来说，这是一本极好的入门读物，是学习所有关键概念并将其应用于案例研究的沉浸式体验。您还可以在这样的学校建立很好的联系。参加目标会议 - 提前准备并突破界限。不要对每个目标化合物进行过度设计/过度设计 - 不要在化合物合成中劝说自己 - 用经验数据测试模型。 始终允许一些 “疯狂 ”的想法来推动新的领域，并允许偶然性 - 许多程序突破都是以这种方式发生的。确保一个想法经过全面测试 - 考虑小型、专注的库，以真正覆盖化学空间来审查概念。不要过度依赖模型——它们是静态配体-受体复合物的模型，可能在生理上相关，也可能不相关。我经常看到一些演讲，一些想法因为与模型不符而被忽视。使用经验数据审查和验证您的模型。基于结构的设计对某些目标来说可能是惊人的，而对其他目标来说则是悲伤的泥潭。平衡。机器学习和 AI 输出也是如此，它们的性能取决于算法的训练集。如果有深度训练数据集可用，则此处将带来巨大的前景。根据我的经验，没有通用的灵丹妙药 — 它就是在正确的时间为正确的项目提供正确的工具。当心万能的灵丹妙药，并受到平台技术的限制——平衡的工具、策略和方法会赢得胜利。创建一个平衡的工具箱并明智地实施。最重要的是：不要只关注化合物效力 - 效力很诱人，很容易通过亲脂性进行设计，但往往以牺牲类似药物的特性为代价。不要将溶解度问题“推向”开发“——开发会停滞不前，成本会上升。平衡配体是进入临床的配体。尽管效力较低，但构建溶解度和未结合组分可以提供具有出色药效学功效的配体。专注于物理化学性质——即使你看到效力被侵蚀——也会没事的。药物发现就是关于平衡——不要过度关注效力或任何单一参数。 最后，我想说对药物化学家最好的建议是尽最大努力设计研究/检测来杀死你的化合物，杀死系列，并杀死靶标/程序。如果您无法这样做，那么您有一个化合物和一个程序，可以顺利地进行开发。我再次唤起了平衡的概念。在成为项目的拥护者之间取得平衡——这是必不可少的——但要平衡这种拥护与不仅要满足候选药物交付指标的愿望，还要扼杀劣质化合物/项目，以确保您在开发中幸存下来并进入临床。如果可能，加入早期开发团队并关注 IND 支持研究，因为您将从所有 CMC（化学、制造和控制）、配方和毒理学工作中学到很多东西。加入 ACS 药物化学部 （ACS MEDI） （https://www.acsmedchem.org/）。志愿者。参与进来。成为由药物化学家和药物猎人组成的庞大而充满活力的社区的一员。加入委员会并帮助规划 ACS 全国会议的 MEDI 讲座会议。参与是在该领域成长的好方法。当您刚开始您的职业生涯时，请寻找一位经验丰富的导师——实际药物发现的知识非常重要，在教科书上找不到;然而，关键的教训/解决方案可以在期刊中找到─阅读！一旦你站稳脚跟并成为自己的领导者，就指导他人。将知识传递下去。永不停止学习 ─ 每天阅读。世界需要新药——世界需要药物化学家——世界需要你。本文尚未被其他出版物引用。