From Complex Natural Products to Simple Synthetic Mimetics by Computational De Novo Design

We present the computational de novo design of synthetically accessible chemical entities that mimic the complex sesquiterpene natural product (?)‐Englerin A. We synthesized lead‐like probes from commercially available building blocks and profiled them for activity against a computationally predicted panel of macromolecular targets. Both the design template (?)‐Englerin A and its low‐molecular weight mimetics presented nanomolar binding affinities and antagonized the transient receptor potential calcium channel TRPM8 in a cell‐based assay, without showing target promiscuity or frequent‐hitter properties. This proof‐of‐concept study outlines an expeditious solution to obtaining natural‐product‐inspired chemical matter with desirable properties.     

从生物有机化学到化学生物学

生物体系中的发现一直是与小分子连系在一起的.生物有机化学是生物学和有机化学相互交叉发展起来的新领域,特别是小分子与蛋白结合后引起蛋白功能变化的研究如抑制作用和活化.化学生物学和结构多样性有机合成使系统研究生物学成为可能,人工转录因子可以用作探针来发现生命过程中新的奥秘.     

Rational De Novo Design of a Cu Metalloenzyme for Superoxide Dismutation

Superoxide dismutases (SODs) are highly efficient enzymes for superoxide dismutation and the first line of defense against oxidative stress. These metalloproteins contain a redox-active metal ion in their active site (Mn, Cu, Fe, Ni) with a tightly controlled reduction potential found in a close range around the optimal value of 0.36 V versus the normal hydrogen electrode (NHE). Rationally designed proteins with well-defined three-dimensional structures offer new opportunities for obtaining functional SOD mimics. Here, we explore four different copper-binding scaffolds: H₃ (His₃), H₄ (His₄), H₂DH (His₃Asp with two His and one Asp in the same plane) and H₃D (His₃Asp with three His in the same plane) by using the scaffold of the de novo protein GRα₃D. EPR and XAS analysis of the resulting copper complexes demonstrates that they are good Cu^II-bound structural mimics of Cu-only SODs. Furthermore, all the complexes exhibit SOD activity, though three orders of magnitude slower than the native enzyme, making them the first de novo copper SOD mimics.     

化学生物学中识别与组装的若干问题

化学与生物学的交叉与融合产生了新学科——化学生物学,开拓了化学和生物学研究的新领域,使人类得以从分子水平来阐释生命过程,揭示生命的奥秘。分子识别和组装是体系的构筑与功能集成的基础,也是自然界生物进行信息存贮、复制和传递的基础,以此来研究构筑具有特定生物学功能的超分子体系,对揭示生命现象和过程具有重要意义。本文结合我们的研究工作从（1）谷胱甘肽过氧化物酶(GPX)模拟与底物识别;（2）医用再生材料与活性支架;（3）类病毒颗粒的组装与解组装3个方面讨论了化学生物学中的识别与组装的意义。     

Multi‐Objective Molecular De Novo Design by Adaptive Fragment Prioritization

We present the development and application of a computational molecular de novo design method for obtaining bioactive compounds with desired on‐ and off‐target binding. The approach translates the nature‐inspired concept of ant colony optimization to combinatorial building block selection. By relying on publicly available structure–activity data, we developed a predictive quantitative polypharmacology model for 640 human drug targets. By taking reductive amination as an example of a privileged reaction, we obtained novel subtype‐selective and multitarget‐modulating dopamine D₄ antagonists, as well as ligands selective for the sigma‐1 receptor with accurately predicted affinities. The nanomolar potencies of the hits obtained, their high ligand efficiencies, and an overall success rate of 90 % demonstrate that this ligand‐based computer‐aided molecular design method may guide target‐focused combinatorial chemistry.     

To Affinity and Beyond: A Personal Reflection on the Design and Discovery of Drugs

Faced with new and as yet unmet medical need, the stark underperformance of the pharmaceutical discovery process is well described if not perfectly understood. Driven primarily by profit rather than societal need, the search for new pharmaceutical products—small molecule drugs, biologicals, and vaccines—is neither properly funded nor sufficiently systematic. Many innovative approaches remain significantly underused and severely underappreciated, while dominant methodologies are replete with problems and limitations. Design is a component of drug discovery that is much discussed but seldom realised. In and of itself, technical innovation alone is unlikely to fulfil all the possibilities of drug discovery if the necessary underlying infrastructure remains unaltered. A fundamental revision in attitudes, with greater reliance on design powered by computational approaches, as well as a move away from the commercial imperative, is thus essential to capitalise fully on the potential of pharmaceutical intervention in healthcare.     

化学多样性空间探索与组合药物设计

本文综述组合化学的最新进展, 内容涵盖组合化学的基本概念、原理、技术, 在药物发现中的应用, 以及组合化学和其他科学技术分枝的关系。最后, 提出了组合化学工程中亟须研究的一些项目, 介绍了开展这些研究所必需的条件, 并给出了解决方案。     

化学学院专业介绍——化学生物学专业

南开大学是国内最早建立化学生物学学科、最早开展化学生物学本科生和研究生培养的高校之一。南开大学化学学院从2012年开始招收化学生物学专业本科生,迄今为止培养了5届共98名毕业生;经过多年教学实践,在化学生物学专业人才培养方面积累了经验,取得了一定成效。介绍了南开大学化学学院化学生物学本科专业的基本情况、课程设置、培养特色和目标、育人成效等。     

Computer-Aided Drug Design Boosts RAS Inhibitor Discovery

The Rat Sarcoma (RAS) family (NRAS, HRAS, and KRAS) is endowed with GTPase activity to regulate various signaling pathways in ubiquitous animal cells. As proto-oncogenes, RAS mutations can maintain activation, leading to the growth and proliferation of abnormal cells and the development of a variety of human cancers. For the fight against tumors, the discovery of RAS-targeted drugs is of high significance. On the one hand, the structural properties of the RAS protein make it difficult to find inhibitors specifically targeted to it. On the other hand, targeting other molecules in the RAS signaling pathway often leads to severe tissue toxicities due to the lack of disease specificity. However, computer-aided drug design (CADD) can help solve the above problems. As an interdisciplinary approach that combines computational biology with medicinal chemistry, CADD has brought a variety of advances and numerous benefits to drug design, such as the rapid identification of new targets and discovery of new drugs. Based on an overview of RAS features and the history of inhibitor discovery, this review provides insight into the application of mainstream CADD methods to RAS drug design.     

Drug Repurposing and De Novo Drug Discovery of Protein Kinase Inhibitors as New Drugs against Schistosomiasis

Schistosomiasis is a neglected tropical disease affecting more than 200 million people worldwide. Chemotherapy relies on one single drug, praziquantel, which is safe but ineffective at killing larval stages of this parasite. Furthermore, concerns have been expressed about the rise in resistance against this drug. In the absence of an antischistosomal vaccine, it is, therefore, necessary to develop new drugs against the different species of schistosomes. Protein kinases are important molecules involved in key cellular processes such as signaling, growth, and differentiation. The kinome of schistosomes has been studied and the suitability of schistosomal protein kinases as targets demonstrated by RNA interference studies. Although protein kinase inhibitors are mostly used in cancer therapy, e.g., for the treatment of chronic myeloid leukemia or melanoma, they are now being increasingly explored for the treatment of non-oncological conditions, including schistosomiasis. Here, we discuss the various approaches including screening of natural and synthetic compounds, de novo drug development, and drug repurposing in the context of the search for protein kinase inhibitors against schistosomiasis. We discuss the status quo of the development of kinase inhibitors against schistosomal serine/threonine kinases such as polo-like kinases (PLKs) and mitogen-activated protein kinases (MAP kinases), as well as protein tyrosine kinases (PTKs).     

Chemical Biology Approaches for Investigating the Functions of Lysine Acetyltransferases

The side‐chain acetylation of lysine residues in histones and non‐histone proteins catalyzed by lysine acetyltransferases (KATs) represents a widespread posttranslational modification (PTM) in the eukaryotic cells. Lysine acetylation plays regulatory roles in major cellular pathways inside and outside the nucleus. In particular, KAT‐mediated histone acetylation has an effect on all DNA‐templated epigenetic processes. Aberrant expression and activation of KATs are commonly observed in human diseases, especially cancer. In recent years, the study of KAT functions in biology and disease has greatly benefited from chemical biology tools and strategies. In this Review, we present the past and current accomplishments in the design of chemical biology approaches for the interrogation of KAT activity and function. These methods and probes are classified according to their mechanisms of action and respective applications, with both strengths and limitations discussed.     

De Novo Design of an Endohedral Heteronuclear Dimetallofullerene (UGd)@C60 with Exceptional Structural and Electronic Properties

Ever since the first synthesis of La@C₈₂ and U@C₂₈, there has been a growing interest in the study of endohedral metallofullerenes (EMFs) because of their great potential in various applications. Here we design a novel heteronuclear EMF (U‐Gd)@C₆₀, by using density functional theory (DFT), which shows an encapsulation energy of about ?5.53 eV, comparable to that of U₂@C_60, La₂@C₈₀, and Lu₂@C₇₆. (U‐Gd)@C₆₀ is found to have a surprising twofold, single‐electron U?Gd bond that results from the strong nanoconfinement of the fullerene, dominated by uranium′s 5f and 6d and gadolinium′s 5d atomic orbitals. The ground state shows an 11‐et high spin state, and the net spins distributed on the U‐pole carbons are relatively scattered, while they are highly concentrated on the Gd‐pole carbons. The exceptional electronic characteristics of this novel EMF, containing both uranium and gadolinium atoms encapsulated, might prove useful for future applications in nuclear energy and biomedicine.     

吉林大学超分子化学生物学学科的建设与发展:从超分子化学到生命机制探索及疫苗、药物研发

吉林大学是国内较早进行化学与生物学交叉研究的高校之一。为了推动吉林大学化学与生物学的深度融合,同时结合本校在超分子化学领域的积累与优势形成研究特色,本校提出了发展超分子化学生物学的构想,并建立了吉林大学超分子化学生物学研究中心。回顾了吉林大学化学与生物学交叉融合的发展历程,介绍了超分子化学生物学学科的发展现状及未来发展方向。     

农药靶标抗性研究在大学化学生物学综合实验中的实践

乙酰羟酸合成酶是目前国际上备受关注的几类超高效商品化除草剂的作用靶标酶,其关键位点的突变是除草剂抗性形成的根源。选择其中2个单点突变体,从分子克隆、突变、蛋白的表达、纯化,到酶学检测等方面,全方位研究了乙酰羟酸合成酶野生型和2个突变体的性质和功能。整套实验包括了多种基本单元操作以及一些具有挑战性的设计性实验,涉及化学生物学的理论与操作较为全面。本实验教学可以使学生从原理上理解农药使用的必要性、农药造成的抗药性以及如何从分子结构的角度设计开发新型绿色农药。     

核酸的有机化学研究在分子生物学发展中的作用

本文主要综述有机化学在建立核酸的顺序测定法和自动顺序仪,在破译遗传密码,在建立核酸片段的化学合成方法,固相合成法及DNA合成仪的设计,在合成许多有生物活力的核酸分子,在发展并完善遗传工程以及新近发现酶RNA(Ribozyme)等方面的卓越贡献。最后简要地展望有机化学将对生物学发展作出进一步贡献的几个方面。     

Chemical Syntheses and Chemical Biology of Carboxyl Polyether Ionophores: Recent Highlights

A central goal of chemical biology is to develop molecular probes that enable fundamental studies of cellular systems. In the hierarchy of bioactive molecules, the so‐called ionophore class occupies an unflattering position in the lower branches, with typical labels being “non‐specific” and “toxic”. In fact, the mere possibility that a candidate molecule possesses “ionophore activity” typically prompts its removal from further studies; ionophores—from a chemical genetics perspective—are molecular outlaws. In stark contrast to this overall poor reputation of ionophores, synthetic chemistry owes some of its most amazing achievements to studies of ionophore natural products, in particular the carboxyl polyethers renowned for their intricate molecular structures. These compounds have for decades been academic battlegrounds where new synthetic methodology is tested and retrosynthetic tactics perfected. Herein, we review the most exciting recent advances in carboxyl polyether ionophore (CPI) synthesis and in addition discuss the burgeoning field of CPI chemical biology.