Development and Testing of New Computational Methods for Ligand Discovery and Mechanism

摘要 长期目标是开发配体发现方法，将其应用于活性生物学问题。 兴趣我们有四个焦点：一。开发新的计算对接方法，在简单的 实验模型系统（由GM 59957支持）。二.这些方法在G蛋白偶联中的应用 受体（GPCR），这是深入研究的生物学，他们赋予，和美妙的模板，为大- 天平对接（U19 GM 106990）。三.药物胶体聚集的机理及影响因素研究 的发现这些小分子胶体是早期发现的人工制品的最大来源， 分子在整个药物开发管道（GM 71630）。四.而我们的前三个焦点采用了 基于目标的配体发现的观点，我们的第四个领域回到经典药理学，采用配体- 基于化学信息学的策略，不寻求为已建立的靶点发现新的配体，而是寻求 已建立的药物和试剂试图预测目标。这个项目一直是公众 化学信息学、数据库和对接的访问工具（GM 71896）。在这里，我们扩展这些项目。I. 发展了新的对接方法，包括处理有序沃茨、共价识别和配体对接 内能应变这些都是实验测试-量热法和晶体学-在模型中 蛀牙部位。二.与Kobilka和Roth实验室合作，我们为GPCR寻找新的化学型，包括µ- 阿片受体、毒蕈碱M2和M3受体以及β2-肾上腺素能受体;特别关注的是 变构配体三.我们深化了对胶体聚集体的物理机制和影响的研究， 关注其在晚期临床候选人中的持久性，其结构和机制，以及 特异性地将胶体药物有效载荷递送至细胞的抗体缀合物。四.工具和数据库 发展仍然是一个重点。化学信息学的一个新方向是全面且 按序列或生物信息学相似性组织的靶标与相同靶标的系统比较 由其配体的相似性组成。初步结果表明，目标对组织的序列，共- 表达或蛋白质-蛋白质相互作用正交于由相似配体相关的对。物理基础是 探讨了

ABSTRACT The long-term goal is to develop ligand discovery methods, applying these to questions of active biological interest. We have four foci: i. development of new computational docking methods, testing these in simple experimental model systems (supported by GM59957). ii. Application of these methods to G Protein Coupled Receptors (GPCRs), which are intensely studied for the biology they confer, and wonderful templates for large- scale docking (U19 GM106990). iii. Investigation of the mechanism and impact of colloidal aggregation in drug discovery. These small molecule colloids, are the greatest source of artifacts in early discovery, and affect molecules throughout the drug development pipeline (GM71630). iv. Whereas our first three foci adopt a target-based view of ligand discovery, our fourth area returns to classical pharmacology, adopting a ligand- based chemoinformatic strategy that seeks not to discover new ligands for established targets, but rather for established drugs and reagents attempts to predict targets. This project has been the venue for the public access tools for chemoinformatics, databases, and docking (GM71896). Here we extend these projects. i. New docking methods are developed, including treating ordered waters, covalent recognition, and ligand internal energy strain. These are tested experimentally—by calorimetry and crystallography—in the model cavity sites. ii. Working with the Kobilka and Roth labs, we seek novel chemotypes for GPCRs including the µ- opioid receptor, the muscarinic M2 and M3 receptors, and the β2-adrenergic receptors; a particular focus are allosteric ligands. iii. We deepen our investigation of the physical mechanism and impact colloidal aggregates, focusing on their persistence among late stage clinical candidates, their structure and mechanism, and antibody conjugates that specifically deliver colloidal drug payloads to cells. iv. Tool and database development remains a key focus. A new direction for the chemoinformatics is a comprehensive and systematic comparison of targets organized by sequence or by bioinformatics similarity, to the same targets organized by the similarity of their ligands. Preliminary results suggest target pairs organized by sequence, co- expression or protein-protein interactions are orthogonal to pairs related by similar ligands. A physical basis is explored.