Pre-computed free energy maps for rapid structure-based ligand design

R43 GM109635 用于基于结构的快速配基设计的预计算自由能图。 配基设计计算方法的成功商业应用需要 既提供定性数据指导设计过程，又提供量化快速生产的平台 用于评估特定配基可能性的数据。在拟议的研究中，一种新的方法--现场-- 配基竞争饱和度鉴定(SILCS)将进一步发展，以提高其实用性 这是一个新兴的计算化学公司SilcsBio LLC的平台。SILCS涉及一个 一次性预先预调适步骤，其中蛋白质、RNA或任何大分子靶标受到 小分子有机溶质水溶液的分子动力学(MD)模拟 归一化和玻尔兹曼变换，产生3D网格自由能(GFE)概率分布，或 GFE FragMaps，包含整个靶标，可用于定性和定量配基 设计方法。在我们第一阶段SBIR成功的基础上，这项第二阶段的提案将侧重于 开发工具以促进SILCS在配体设计中的应用，进一步提高 该方法，以及该技术在预测大分子相互作用方面的扩展， 包括蛋白质与蛋白质的相互作用。目标1是开发工具来执行广泛的化学 允许快速、无缝地定量评估数千个配体的3D相互作用的转换 每天都有一个目标。这些工具将与现有的CHARMM通用力场集成在一起 该计划还将为开发新型化学IP提供基于片段的设计能力。目标2是 通过以下方式提高精度：在振荡的μex大正则蒙特式基础上添加远程静电 卡洛(GCMC)技术，已经成功地对深度或闭塞的口袋进行采样，例如在GPCR和 核受体；通过哈密顿复制交换增强目标蛋白的构象采样 MD方法(HREMD)；包括通过使用经典的Drude可极化力场来计算电子极化率 SILCS GFE碎片图的计算和改进的GFE领域中配体的构象采样 碎片地图。AIM 3将利用GFE FragMaps中编码的信息开发一个 大分子对接实用工具，它将解释在对接过程中单体构象的异质性 一个大分子与另一个大分子相互连接，用于预测由，例如， 两种或两种以上的蛋白质。实现与这些科学目标相关的里程碑将直接推动我们的 SilcsBio LLC的商业化战略，通过提高与所有三大 业务目标：1)直接向配基设计交付SILCS GFE FragMap和/或SILCS软件 (例如制药)内部使用的公司，2)与计算化学软件合作 让更多配基设计公司能够使用SILCS技术的供应商和3) SilcsBio LLC作为合同研究组织(CRO)进行基于结构的配体设计。

R43 GM109635 Pre-computed free energy maps for rapid structure-based ligand design. Project Summary Successful commercial application of computational methods for ligand design requires a platform that provides both qualitative data to direct the design process and rapid production of quantitative data to allow for evaluation of specific ligand possibilities. In the proposed study a novel approach, Site- Identification by Ligand Competitive Saturation (SILCS), will be further developed to improve its utility as such a platform in the context of the emerging computational chemistry company SilcsBio LLC. SILCS involves a one-time up-front pre-conditioning step where the protein, RNA or any macromolecular target is subjected to molecular dynamics (MD) simulations in an aqueous solution of small organic solutes that, following normalization and Boltzmann transformation, yields 3D Grid Free Energy (GFE) probability distributions, or GFE FragMaps, that encompass the entire target and may be used for both qualitative and quantitative ligand design approaches. Building upon our successes in the Phase I SBIR, this Phase II proposal will focus on development of tools to facilitate the application of SILCS to ligand design, further improving the accuracy of the methodology, and the extension of the technology to the prediction of macromolecular interactions, including protein-protein interactions. Aim 1 is the development of tools to perform a wide range of chemical transformations allowing for rapid, seamless quantitative evaluation of the 3D interaction of 1000s of ligands with a target on a daily basis. The tools will be integrated with the existing CHARMM General Force Field program to also provide fragment-based design capabilities for the development of novel chemical IP. Aim 2 is improvement in accuracy by: adding long-range electrostatics to our oscillating μex Grand-Canonical Monte Carlo (GCMC) technology that already successfully samples deep or occluded pockets such as in GPCRs and nuclear receptors; enhancing conformational sampling of the target protein by Hamiltonian Replica Exchange MD methods (HREMD); including electronic polarizability by using the classical Drude polarizable force field for calculation of SILCS GFE FragMaps; and improved conformational sampling of ligands in the field of the GFE FragMaps. Aim 3 will take advantage of the information encoded in the GFE FragMaps to develop a macromolecular docking utility that will account for monomer conformational heterogeneity during docking of one macromolecule with another, for the prediction of the 3D structure of complexes consisting of, for example, two or more proteins. Meeting the milestones associated with these scientific Aims will directly further our commercialization strategy for SilcsBio LLC by enhancing the value associated with all three of the major business Aims: 1) direct delivery of SILCS GFE FragMaps and/or the SILCS software directly to ligand-design (e.g. pharmaceutical) companies for in-house use, 2) partnering with computational chemistry software vendors to make the SILCS technology accessible to a wider range of ligand-design companies and 3) SilcsBio LLC acting as a contract research organization (CRO) performing structure-based ligand design.