针对当前发现药物新靶标和新颖结构先导化合物日益困难、严重制约原创性药物研发的现状，运用计算生物学和药物分子设计等理论方法，与药物化学生物学和药理学等实验技术紧密结合，开展了理论模拟驱动的靶标新功能发现、药物作用机理研究和创新药物研发。揭示了多个重要靶标的调控机制，发现了一批具有重要开发前景的先导化合物，其中两个已被确定为候选新药进入临床前评价。共发表SCI论文118篇，总影响因子>700，他引1831次。近5年内，主持863、基金委等项目7项，在Nature、Nature Chem、JACS、PNAS、Nucleic Acid Res和JMC等杂志发表通讯、共同通讯或第一作者SCI论文53篇（IF>9论文9篇，IF>5论文17篇）。另通过合作研究，在Science、Nature及其子刊等杂志发表论文42篇；合作申请专利12项 (美国专利1项、PCT两项)，已授权4项（1项实现授权转让）。

Currently, the discovery of new targets and lead compounds with novel structures was faced with enormous difficulties, which severely restricted the development of innovative drugs. In response to this situation, the discovery of novel functions of targets, research of mechanism of drug actions, and development for innovative drugs were launched, with a series of theoretical methods from computational biology and molecular drug design applied, in tight combination with the experimental technologies from chemical biology and pharmacology. As a consequence, the regulatory mechanism of several important targets were revealed, together with the discovery of a bunch of lead compounds with considerable development prospect, among which two compounds are under the preclinical evaluation as drug candidates. A total of 118 SCI papers were published, with cumulative impact factors above 700, and other citations 1831. In the recent five years, 7 projects were presided over including 863 and NSFC sources, along with 53 SCI papers (9 papers IF>9, 17 papers IF>5) in which he served as corresponding author, co-corresponding author or first author, on the journals of Nature, Nature Chem, JACS, PNAS, Nucleic Acid Res and JMC. In addition, 42 SCI papers were published on the journals of Science, Nature and other Nature-branched primary research journals, through collaborative research with both domestic and international institutions. 12 collaborative patent applications have been submitted (1 US Patent, 2 PCT), and four patents have already been licensed (1 with successful authorized transfer).

本研究计划围绕病毒抗药性和肿瘤耐药性等焦点和难点问题，着重开发以蛋白-蛋白相互作用为新的药物靶标，推进多靶点抑制剂的发现和结构优化研究，为长期有效治疗病毒感染性疾病和肿瘤提供新的设计思路和新结构新机制候选药物。以蛋白-蛋白相互作用干预为主要策略，在多靶点干预思想的指导下，我们以HIV-1整合酶、介导HIV-1入侵的宿主细胞受体CCR5/CXCR4和病毒被膜糖蛋白gp120，以及肝细胞生长因子受体c-Met和表观遗传学蛋白Bromodomain为靶标，并新增了抗糖尿病药物新靶标GPR40受体，开展了多重HIV-1整合酶抑制剂、双功能gp120/CCR5 融合抑制剂、整合酶/ CXCR4双靶点抑制剂、成药性c-MET激酶/Bromodomain双重抑制剂、双通道激活促胰岛素分泌信号通路的GPR40小分子激动剂的发现和功能研究，以及基于C-H活化策略/基于天然产物骨架重组的类药性优势骨架的绿色化学合成方法学、基于构像约束策略的多肽类蛋白-蛋白相互作用抑制剂成药性结构优化方法研究。建立了靶向非酶结合位点(蛋白-蛋白相互作用界面或变构位点或非活性构像)以及协同靶向多个位点/蛋白的新型抑制剂的药物发现新方法，获得了进入临床前研究的抗病毒和抗肿瘤候选药物，其中多重HIV-1整合酶抑制剂NLH-29同时靶向整合酶的二聚、催化核心及其与细胞辅因子LEDGF/p75的相互作用，表现出治疗指数高达10000的抗病毒疗效，对耐药性HIV病毒株有效抑制；第一个c-Met激酶/溴结构功能域双重抑制剂LXM-262，逆转非小细胞肺癌细胞的获得性c-Met耐药，并表现出10-50倍强效于阳性药Cabozantinib和Crizotinib的口服体内抑瘤活性，治疗窗大于50倍。在构建小分子蛋白-蛋白相互作用抑制剂骨架的方法学研究方面，建立了无金属参与的基于C-H直接官能团化以及C-C断键的杂芳环优势骨架的绿色合成方法，开创了基于天然产物青蒿素结构重组的杂芳环优势骨架化合物库的构建，并成功应用于抗肿瘤小分子SMO抑制剂的发现研究。发表了20篇SCI论文，SCI引用180次；申请发明专利5项, 申请PCT国际专利1项，获得12项中国发明专利授权。培养了3名博士、11名硕士、1名博士后、1名副研。作为大会主席，成功举办了第十四届中国国际多肽学术会议暨第五届亚太国际多肽学术会议，国内外参会代表400多人。