挑战:

• SARM1具显著的动态构象变化，体外难以稳定并捕捉其激活态构象；
• 目前的候选药物分子主要为竞争性抑制剂，缺乏明确的抑制机制。

目标:

• 通过晶泰科技AI驱动的Cryo-EM图像处理模块，帮助加速解析抑制剂与SARM1的高分辨率电镜结构，为理性药物设计提供新思路、新方向；
• 进一步揭示该靶点的自抑制态与激活态的转换机制，加深对靶点作用机理的理解。

结构解析流程：

解析结果：

项目小结：

仅使用200kV电镜，在8 周内成功解析SARM1与抑制剂的2.8 Å结构，这项开创性研究成果揭示了一种小分子抑制剂的竞争性抑制机制。高比例NMN/NAD+诱导激活SARM1，抑制剂在SARM1催化下与NAD+发生碱基交换反应，生成抑制剂-ADPR这一新产物，该产物与SARM1结合并锁定其处于激活态构象，封锁底物NAD+结合口袋，从而抑制SARM1的NAD+降解活性。该结果为证实SARM1的激活机制和碱基交换反应提供了最直接的结构证据。

数据计算过程中，通过使用 AI 驱动的图像处理模块实现了目标颗粒的精确挑选，与经典方法相比，在同等算力下，加速整体计算流程并实现更高的分辨率。

同时，首次从分子水平揭示了 SARM1 的激活机制，加深对其如何介导退行性疾病发生机理的理解。

The post 8周解析SARM1蛋白结构 appeared first on 晶泰科技 XtalPi.

Case Study: How XtalPi Used Diversity Library of 80K Compounds to Find Hits Targeting FGFR3 

Mutations in Fibroblast Growth Factor Receptor 3 (FGFR3) are linked to various cancers, making it a critical target for therapeutic intervention. But targeting specific FGFR members individually is very challenging due to their structural similarities. Currently only pan-inhibitors are approved by the FDA.

In an effort to selectively target FGFR3, XtalPi sought to identify novel scaffolds using our curated high-throughput screening (HTS) diversity library.

Our Key Results:

• Discovery of 15 potent hit compounds, each exhibiting biochemical potency with IC₅₀ values below 10 μM.
• Identified three hit series which possessed novel scaffolds that are distinct from those of known FGFR3 inhibitors, providing new avenues for selectively targeting the protein.

The post Identifying Novel FGFR3 Inhibitors By XtalPi-Curated HTS Diversity Library appeared first on 晶泰科技 XtalPi.

Case Study: How the XtalPi Team Discovered Novel, Non-Covalent, Potent Hits Against GPX4 in 28 Days

GPX4 is a critical enzyme for cellular antioxidant defense, but is a highly challenging target. In this case study, we share the story of how we discovered three novel non-covalent hit compounds with biochemical IC₅₀ < 10µM in just 28 days.

• Using predictive AI models and physics-based computations, we probed key pharmacophores with high accuracy and throughput, even without reference compounds.
• 159 library compounds were proposed and 124 were successfully synthesized using our automation platform.

The post Hit Identification – Novel Hits for GPX4 appeared first on 晶泰科技 XtalPi.

Case Study: How the XtalPi Team Discovered a Selective, Novel Lead Series for Key Cancer Target SMARCA2

Loss-of-function mutations in SMARCA4 occur in various cancers, leading to an increased dependency on the structurally similar SMARCA2 for activity. This makes SMARCA2 an attractive therapeutic target due to its increased importance in cancer cell survival.

However, identifying novel small-molecule SMARCA2-selective inhibitors poses significant challenges. To address this, XtalPi leveraged its advanced AI-powered discovery platform and Cryo-EM technology, opening up new possibilities for targeted cancer treatments.

Our Key Results: 

• Discovered a novel lead series with high efficacy and 20-fold selectivity for SMARCA2 over SMARCA4 in biochemical assays, showcasing strong potential for further development.
• Identified a unique SMARCA2 binding pocket using Cryo-EM at 2.9 Å resolution, offering new insights for the design of selective inhibitors and advancing structure-based drug discovery.
• Achieved 100% library compound synthetic success rate by proprietary synthetic feasibility prediction models.

The post Lead Identification – Discovering Selective Inhibitors Against an Unreported Binding Pocket of SMARCA2 via a Rational Drug Design Approach appeared first on 晶泰科技 XtalPi.