2周完成数月的工作！药明康德正为药物发现批量按下“快进键” | Bilingual

过去几年，分子胶正逐渐成为药物发现的重要方向。与传统小分子不同，分子胶不需要占据蛋白结合口袋来发挥作用。这种独特的机制将大量过去认为“不可成药”靶点拉入可治疗范畴，也让分子胶的发现之路面临诸多挑战。

由于分子胶通常依赖诱导蛋白之间形成新的相互作用，其活性难以直接预测，许多候选分子的发现仍高度依赖大规模筛选与反复验证。在传统的药物发现流程中，这意味着分子胶的优化通常需要经历多轮“设计-合成-测试”迭代，而每一轮的周期往往以月为单位计算。

例如，单次分子胶合成往往需要一个多月时间，获得目标化合物后还需经过分离纯化才能进入后续环节；随后的生物学测试也至少需要两周。再加上不同环节之间的转移与衔接等耗时，这些因素制约了分子胶的发现效率，同时也增加了项目的不确定性。

在赋能客户的历程中，药明康德生物学平台（WuXi Biology）团队对于客户面临的这一困境深有体会。为了帮助客户突破分子发现的瓶颈，药明康德生物学平台整合了多年来在药物化学、高通量化学、高通量筛选和计算机辅助药物设计等方面积累的能力，搭建了D2B（Direct-to-Biology）平台。

借助这一模式，当客户带着分子胶项目找到药明康德生物学平台时，过去需要数月才能完成的一轮“设计-合成-测试”流程，如今被压缩至2-3周，大幅加速了药物发现进程。

“D2B在苗头化合物扩展和先导化合物优化阶段尤为有效，”谈及D2B能力在早期药物发现中的作用，药明康德研发生物学平台负责人、生物学业务平台能力中心负责人苏文姬博士指出，“在早期阶段，团队通常需要评估数百到数千个化合物，而D2B提供了一种更具成本效益的模式，能够有效加速项目进程。”

要理解效率提升从何而来，需要进一步回到D2B这一核心能力本身。

D2B重构“设计-合成-筛选”路径

D2B平台的核心，在于将微型化的化学合成与生物筛选整合为一个连续流程。为此，团队整合了高通量化学合成团队的小体积合成能力，以及高通量筛选团队的微型化生物实验、自动化系统等能力。

在D2B模式中，化学反应被转移至384孔或1536孔的微孔板体系中进行。每一个孔都相当于一个独立的微型反应单元，在极小体积条件下并行开展大量化学合成。

在这一过程中，分子在完成合成后，可以直接进入后续的筛选检测流程，而无需经历传统模式下的分离纯化环节，从而使“设计-合成-测试”这一连续过程更加快速地推进。

由于省去了分离纯化步骤，反应体系中的杂质将不可避免地进入生物检测环节。如何确保这些杂质不会干扰下游检测和结果解读，成为D2B平台建设的另一项关键考验。

苏文姬博士介绍，围绕这一挑战，团队从多个环节进行了系统性优化。例如，团队对化学反应条件进行开发与优化，以采用转化率更高的反应体系；同时，对研究材料进行筛选分析，以尽可能降低杂质比例。此外，团队还优化了检测条件和数据解读方法，用以评估不同杂质水平和反应条件对下游检测结果的影响，提升结果解读的可靠性。

相比于传统模式，搭载D2B能力的一体化筛选平台，使高通量筛选得到的化合物无需“绕路”，即可直接进入生物检测流程，从而缩短了整体流程周期。最终，设计-合成-测试流程得以被压缩至2~3周完成一个迭代周期，从而帮助研究团队更快获得结构-活性关系信息，为后续优化与决策提供及时支持。

图片来源：123RF

面向复杂分子时代：D2B的应用拓展

如今，面对越来越复杂的新型分子需求，D2B也能够更加高效地赋能早期发现与优化工作。

“D2B尤其适用于分子胶等靶向蛋白降解分子、肽类、抗体偶联药物（ADC）与抗体-寡核苷酸偶联物（AOC）等偶联分子的发现，”苏文姬博士指出，“这些分子类型在项目初期需要大量组合化学研究，而D2B平台提供了一种加速这些项目的新工具。”

除了文章开头提到的分子胶项目，药明康德生物学平台的D2B能力也已被应用于其他复杂分子的早期发现与优化。

例如，一家客户在推进一款蛋白降解靶向嵌合体项目时，就遇到了典型的细胞透膜性瓶颈。这类化合物的分子量大、极性强，因此在细胞膜通透性方面天然面临挑战。尽管候选分子在体外表现出良好的靶点结合能力，但细胞活性提升始终受限。

当项目陷入瓶颈，客户找到了药明康德。基于对客户已有分子结构特征及靶点信息的分析，药明康德生物学平台团队利用D2B的高通量组合化学特性，在一个月内完成了2000个分子的设计合成和检测，为后续优化提供了新的设计思路，并推动项目进入下一阶段的迭代优化。

D2B的应用价值不仅体现在提升复杂分子的优化效率，在药物发现早期，它还能够支持研究团队探索更广阔的化学空间。

一位客户计划针对一个难成药靶点开展筛选研究，但现有市售化合物库难以满足项目需求。相比从现有化合物中寻找有限的可能性，客户更希望围绕靶点特征快速构建定制化化合物库，以提高发现苗头化合物的概率。

基于D2B平台的高通量组合化学能力，药明康德生物学平台团队能够在两个月内完成超过20万个化合物的设计与合成，并同步开展筛选工作。通过大幅拓展可探索的化学空间，项目能够获得更多潜在活性分子，也显著提升了苗头化合物发现的成功率。

D2B的下一步

如今，随着药物研发不断向新靶点、新机制和新分子类型拓展，药物发现对化学空间探索速度和广度的要求也在持续提升。在这一背景下，D2B平台本身也在不断演进，以适应更加多样化的研发需求。

苏文姬博士介绍，反应类型的丰富程度是决定D2B能力边界的重要因素之一。由于能够直接适用于微型化体系的化学反应相对有限，团队正在持续开发和优化反应条件，使更多常用反应能够兼容D2B模式。目前，团队已经开发了多种药物化学项目中常用的反应，包括偶联反应和酰胺键形成反应，并且持续探索新的反应，将其纳入D2B工作流程。

与此同时，团队也在不断扩展可用于D2B项目的化学砌块资源。依托过去几年积累的砌块库，团队正在进行筛选、收集验证数据，进一步拓展平台能够覆盖的化学空间。

随着药物发现不断向更复杂的分子和更具挑战性的靶点迈进，能够快速探索化学空间、加速实验反馈的D2B平台，有望在未来的药物发现中发挥更关键的作用。作为药明康德一体化药物发现能力体系的重要一环，D2B正在与多个技术平台形成协同，助力客户更高效地将科学设想转化为可验证的成果。

▲欲了解WuXi Biology如何赋能药物研发，请长按扫描上方二维码，与药明康德生物学业务平台联系

How does WuXi AppTec's Direct-to-Biology (D2B) capability accelerate drug discovery?

WuXi AppTec has built the Direct-to-Biology (D2B) system, which integrates years of expertise such as medicinal chemistry, high-throughput chemistry, high-throughput screening, and computer-aided drug design into a continuous workflow. With the D2B capability, the design-synthesis-test cycle of a molecular glue program can be compressed from months to 2-3 weeks.

In recent years, molecular glues have emerged as a promising modality in drug discovery.Unlike conventional small molecules, molecular glues do not need to occupy binding pockets to function. This unique mechanism renders many previously "undruggable" targets accessible, but it also presents significant discovery challenges.

Because molecular glues typically work by inducing novel protein-protein interactions, their activities are difficult to predict directly. The discovery of candidate molecules still relies heavily on large-scale screening and iterative validation. In traditional drug discovery workflows, optimizing a molecular glue requires multiple rounds of “design-synthesis-testing”.

D2B Compresses the Design-Synthesis-Testing Cycle

The team in WuXi Biology, a business unit of WuXi AppTec, integrated capabilities accumulated over years to build the D2B system. With this model, when a client brings a molecular glue program to WuXi Biology,a design-synthesis-test cycle that used to take months can now be compressed to 2-3 weeks, significantly accelerating drug discovery.

"D2B is particularly powerful in hit expansion and hit-to-lead stages," said Dr. Wenji Su, Head of Discovery Biology Platform at WuXi AppTec. "At early stages, teams often need to assess hundreds to thousands of compounds, and D2B provides a more cost-effective way to accelerate these projects."

The D2B platform integrates miniaturized chemical synthesis and biological screening into a continuous workflow. To achieve this, the team combined the small-volume synthesis capabilities of the high-throughput chemistry team with the miniaturized bioassays and automation systems of the high-throughput screening team.

In the D2B model, chemical reactions are transferred into 384-well or 1536-well microplates. Each well acts as an independent miniaturized reaction unit, allowing a large number of chemical syntheses to run in parallel at very small volumes.

Once synthesis is completed, molecules can move directly into subsequent screening without going through traditional separation and purification steps, thereby accelerating the continuous design-synthesis-test cycle.

With the separation and purification step eliminated, impurities from the reaction system inevitably enter the biological testing stage. Ensuring that these impurities do not interfere with downstream assays became another key challenge in building the D2B platform.

Dr. Su explained that the team systematically optimized multiple aspects to address this challenge. For example, the team developed and optimized chemical reaction conditions to achieve higher conversion rates, while analyzing and selecting research materials to minimize impurity levels. Additionally, the team optimized assay conditions to evaluate the impact of different impurity levels and reaction conditions on downstream results.

Compared to traditional models, the D2B capability allows compounds to proceed from high-throughput screening to biological testing without "detours," shortening the overall cycle.

Image source: 123RF

Expanding D2B Applications to New Modalities

As drug discovery faces increasingly complex novel molecular modalities, WuXi Biology’s D2B platform is also enabling more efficient early discovery and optimization. "In terms of applicable modalities, D2B is mostly suitable for TPD discovery, molecular glue, peptide, and conjugates including ADC, AOC, and others," Dr. Su noted, "Many of these molecules require extensive combinatorial studies at the beginning of projects, and D2B provides a more cost-effective way to accelerate these projects.”

Beyond the molecular glue example mentioned earlier, WuXi Biology's D2B capability has also been applied to the early discovery and optimization of other complex molecules.

In one case, a client advancing a TPD program encountered a typical cell membrane permeability bottleneck. These compounds have large molecular weights and high polarity, making cell membrane permeability an inherent challenge. Although candidate molecules showed ideal in vitro target binding, their cellular activity remained limited.

When the program encountered a bottleneck, the client approached WuXi AppTec. Based on an analysis of the client's molecular structures and target information,the WuXi Biology team leveraged D2B's high-throughput combinatorial chemistry capabilities to complete the design, synthesis, and testing of 2,000 molecules within one month. This provided new ideas for subsequent optimization and moved the program into further iteration.

The value of D2B also extends to exploring broader chemical space in early drug discovery. A client initiated a screening campaign against a difficult-to-drug target, but found that existing commercial compound libraries could not meet the project's needs. Rather than relying on the limited potential of off-the-shelf compounds, the client wanted to rapidly build customized compound libraries based on target characteristics to increase the probability of hit finding.

Using D2B's high-throughput combinatorial chemistry capabilities, the WuXi Biology team designed and synthesized more than 200,000 compounds within two months while simultaneously conducting screening. By significantly expanding the chemical space, the project obtained more potentially active molecules and notably increased the success rate of hit discovery.

The Next Frontier for D2B: Expanding Reaction Types

As drug discovery continues to expand into new targets, mechanisms, and molecular modalities, the need for speed and breadth in exploring chemical space keeps growing. Against this backdrop, the D2B platform itself is continuously evolving to meet more diverse demands.

Dr. Su noted that the variety of reaction types is a key factor defining the boundaries of D2B capability.Since only a limited set of chemical reactions can be directly adapted to miniaturized systems, the team is continuously developing and optimizing reaction conditions to enable more commonly used reactions to be compatible with the D2B model.

To date, the team has developed multiple reaction types commonly used in medicinal chemistry projects, including coupling reactions and amide bond formation, and continues to explore new reactions to incorporate into the D2B workflow.

At the same time, the team is continuously expanding the chemical building block resources available for D2B projects. Leveraging the building block library accumulated over the years, the team is further expanding the chemical space that the platform can cover.

As drug discovery moves toward complex molecules and challenging targets, the D2B platform is expected to play an important role. As part of WuXi AppTec's integrated drug discovery capability system, D2B is creating synergies with multiple technology platforms, enabling clients to transform scientific ideas into verifiable results more efficiently.

Key Takeaways

• Team in WuXi Biology, a business unit of WuXi AppTec, integrated capabilities accumulated over years such as medicinal chemistry, high-throughput chemistry, high-throughput screening, and computer-aided drug design into a continuous workflow, establishing the D2B system.

• By integrating miniaturized synthesis and screening in microplates, WuXi Biology’s D2B platform compresses the design-synthesis-test cycle of a molecular glue program from months to 2-3 weeks.

• WuXi Biology’s D2B platform has been validated across complex molecular modalities. The platform has helped clients complete the synthesis and testing of thousands of molecules in weeks, addressing challenges such as cell permeability.

• In a case study, team in WuXi Biology designed and synthesized over 200,000 compounds in two months for a difficult-to-drug target, significantly expanding chemical space and increasing hit discovery success rates.

• WuXi AppTec is systematically developing more compatible reactions and building block libraries to support broader discovery needs.

免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

版权说明：欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。