Prediction methods and databases within chemoinformatics: emphasis on drugs and drug candidates

MOTIVATION: To gather information about available databases and chemoinformatics methods for prediction of properties relevant to the drug discovery and optimization process. RESULTS: We present an overview of the most important databases with 2-dimensional and 3-dimensional structural information about drugs and drug candidates, and of databases with relevant properties. Access to experimental data and numerical methods for selecting and utilizing these data is crucial for developing accurate predictive in silico models. Many interesting predictive methods for classifying the suitability of chemical compounds as potential drugs, as well as for predicting their physico-chemical and ADMET properties have been proposed in recent years. These methods are discussed, and some possible future directions in this rapidly developing field are described.     

Towards predictive resistance models for agrochemicals by combining chemical and protein similarity via proteochemometric modelling

Resistance to pesticides is an increasing problem in agriculture. Despite practices such as phased use and cycling of ‘orthogonally resistant’ agents, resistance remains a major risk to national and global food security. To combat this problem, there is a need for both new approaches for pesticide design, as well as for novel chemical entities themselves. As summarized in this opinion article, a technique termed ‘proteochemometric modelling’ (PCM), from the field of chemoinformatics, could aid in the quantification and prediction of resistance that acts via point mutations in the target proteins of an agent. The technique combines information from both the chemical and biological domain to generate bioactivity models across large numbers of ligands as well as protein targets. PCM has previously been validated in prospective, experimental work in the medicinal chemistry area, and it draws on the growing amount of bioactivity information available in the public domain. Here, two potential applications of proteochemometric modelling to agrochemical data are described, based on previously published examples from the medicinal chemistry literature.     

植物microRNA的生物合成和调控功能

植物microRNA(miRNA)是一类21～24个核苷酸长度的小RNA分子。它的生物合成机制及其对植物生长发育的重要调控作用是人们普遍关注的科学问题和深入探索的研究对象。目前,RNA分子生物学在理论和技术上日趋完善,正在成为一门独立的新兴学科,对生物相关学科的发展产生了重要影响。其中,植物miRNA的生物合成和调控功能是植物小RNA分子生物学的核心问题之一。该文提供植物miRNA领域的最新研究成果,在此基础上对未来的学科发展提出新的建议。     

Interrelations of Graph Distance Measures Based on Topological Indices

In this paper, we derive interrelations of graph distance measures by means of inequalities. For this investigation we are using graph distance measures based on topological indices that have not been studied in this context. Specifically, we are using the well-known Wiener index, Randić index, eigenvalue-based quantities and graph entropies. In addition to this analysis, we present results from numerical studies exploring various properties of the measures and aspects of their quality. Our results could find application in chemoinformatics and computational biology where the structural investigation of chemical components and gene networks is currently of great interest.     

Bugs in computational chemistry software and their consequences: the importance of the source code

The increase in computer power and the development of new mathematical concepts implemented in software have allowed computational chemistry to emerge as a new research field. Although programs were freely distributed during the "golden age" of this discipline, today they are usually copyrighted and have become easier and easier to use through sophisticated graphical interfaces. This "democratization" is a vector of success for this discipline. Nowadays, non-theoreticians can use such programs more easily and solve chemistry-related problems with the computer. The number of program offerings has rapidly grown and private companies specialized in molecular modeling have appeared and compete to sell their products. Thus, numerous software packages, often presenting similar capabilities, are now available on the market. Within this context, the availability of the program source code remains, in our opinion, an important criterion for program selection.     

A combined bioinformatics and chemoinformatics approach for the development of new antiparasitic drugs

A modern concept for the development of novel antiparasitic drugs is the combination of bioinformatics and chemoinformatics approaches. This covers, for example, the identification of target proteins serving as molecular points of attack for parasiticides--the idea is that, owing to some essential role, inhibition of a target protein should eradicate the parasite. To prevent toxicity problems for vertebrate host organisms, it is advantageous that these proteins show significant differences from their vertebrate counterparts. In the present work, we identified potential target proteins in parasitic nematodes (Ascaris suum, Brugia malayi, and Haemonchus contortus) and arthropods (Boophilus microplus and Rhipicephalus appendiculatus) using bioinformatic sequence comparison methods on expressed sequence tags. Interesting target proteins (e.g., S-adenosyl-l-methionine synthetase) were characterized in detail by subjecting them to in-depth bioinformatic analysis. S-Adenosyl-l-methionine synthetase was also used to elucidate chemoinformatics approaches like homology modeling and docking, which represent appropriate methods for generating valuable data for the development of new drug candidates.     

Implementing relevance feedback in ligand-based virtual screening using Bayesian inference network

Recently, the use of the Bayesian network as an alternative to existing tools for similarity-based virtual screening has received noticeable attention from researchers in the chemoinformatics field. The main aim of the Bayesian network model is to improve the retrieval effectiveness of similarity-based virtual screening. To this end, different models of the Bayesian network have been developed. In our previous works, the retrieval performance of the Bayesian network was observed to improve significantly when multiple reference structures or fragment weightings were used. In this article, the authors enhance the Bayesian inference network (BIN) using the relevance feedback information. In this approach, a few high-ranking structures of unknown activity were filtered from the outputs of BIN, based on a single active reference structure, to form a set of active reference structures. This set of active reference structures was used in two distinct techniques for carrying out such BIN searching: reweighting the fragments in the reference structures and group fusion techniques. Simulated virtual screening experiments with three MDL Drug Data Report data sets showed that the proposed techniques provide simple ways of enhancing the cost-effectiveness of ligand-based virtual screening searches, especially for higher diversity data sets.     

The end of Invasion Biology: intellectual debate does not equate to nonsensical science

Valéry et al. recently proposed to end the field of Invasion Biology on the grounds that it is based on an inadequate definition of the concept of biological invasion and that, as exotic species, native species should also be called invasive whenever they outbreak. We argue, on the contrary, that the sudden demographic dominance of native species cannot be termed invasion. Moreover, we claim that the suggestion of ending a fruitful and useful discipline because it does not conform to a subjective definition or because it still encompasses some debatable ideas and unresolved questions is both irrelevant and excessive. We believe that the thousands of researchers working in this discipline do not perform nonsensical science, and that their efforts to understand and limit biological invasions are compatible with debating on the key concept of that field.     

Key informants on the history of anthropology

The history of anthropology is a growing field of study within the discipline itself. Our series ‘Key Informants on the History of Anthropology’ is offered as a contribution to the discussion of how anthropology, as it is understood and practised today, evolved and took shape. In this invited contribution, T. O. Beidelman reflects on the formative, enlightening and sometimes dramatic encounters and experiences that have shaped his engagement with anthropology, and have influenced his many and lasting contributions to the discipline.     

Can we rationally design promiscuous drugs?

Structure-based drug design is now used widely in modern medicinal chemistry. The application of structural biology to medicinal chemistry has heralded the "rational drug design" vision of discovering exquisitely selective ligands. However, recent advances in post-genomic biology are indicating that polypharmacology may be a necessary trait for the efficacy of many drugs, therefore questioning the "one drug, one target" assumption of current rational drug design. By combining advances in chemoinformatics and structural biology, it might be possible to rationally design the next generation of promiscuous drugs with polypharmacology.     

Importance of the 5′ regulatory region to bacterial synthetic biology applications

The field of synthetic biology is evolving at a fast pace. It is advancing beyond single-gene alterations in single hosts to the logical design of complex circuits and the development of integrated synthetic genomes. Recent breakthroughs in deep learning, which is increasingly used in de novo assembly of DNA components with predictable effects, are also aiding the discipline. Despite advances in computing, the field is still reliant on the availability of pre-characterized DNA parts, whether natural or synthetic, to regulate gene expression in bacteria and make valuable compounds. In this review, we discuss the different bacterial synthetic biology methodologies employed in the creation of 5′ regulatory regions – promoters, untranslated regions and 5′-end of coding sequences. We summarize methodologies and discuss their significance for each of the functional DNA components, and highlight the key advances made in bacterial engineering by concentrating on their flaws and strengths. We end the review by outlining the issues that the discipline may face in the near future.     

华南生态秀河山

文章以作者30年来在华南植物研究所生态学研究的工作与部分成果,反映了中国科学院华南植物研究所30年来生态学科发展的趋势,并以折射广东省生态学会成立30年来生态学科之发展。文章综述认为,华南植物研究所生态科学的发展,与广东省乃至中国生态学学科发展是同步的,经历着由面上研究向定位研究的发展,定性研究向定量研究的发展,野外调查研究向野外实验生态研究的发展,以及中观研究向微观与宏观研究的发展。期间广东省的生态学工作者为学科的发展与社会的进步做出了重要的贡献。     

Asymmetric Clustering Index in a Case Study of 5-HT1A Receptor Ligands

The automatic clustering of chemical compounds is an important branch of chemoinformatics. In this paper the Asymmetric Clustering Index (Aci) is proposed to assess how well an automatically created partition reflects the reference. The asymmetry allows for a distinction between the fixed reference and the numerically constructed partition. The introduced index is applied to evaluate the quality of hierarchical clustering procedures for 5-HT_1A receptor ligands. We find that the most appropriate combination of parameters for the hierarchical clustering of compounds with a determined activity for this biological target is the Klekota Roth fingerprint combined with the complete linkage function and the Buser similarity metric.     

The emergence of ecological engineering as a discipline

Pioneering efforts in ecological engineering (a precedent setting engineering and applied science discipline in which the self-engineering capabilities of ecosystems are managed for the benefit of the environment and humankind) research and practice have proven to be tremendous strides toward establishing a new engineering discipline with a science base in ecology. Case studies, demonstrations and applications pertaining to restoration, rehabilitation, conservation, sustainability, reconstruction, remediation and reclamation of ecosystems using ecological engineering techniques are numerous. This has brought the field to the current level where many scientists and engineers adequately support the concept of, and need for, ecological engineering, and generally agree that ecological engineering has been sufficiently defined. There is also general agreement that full emergence as an engineering discipline remains a difficult task. Certain general characteristics of existing engineering disciplines can guide the emergence of ecological engineering and thus are a vital context covered in this paper. From the context of engineering practice, three concepts are evident including: (1) establishment of formal foundations for ecological engineering research and development; (2) development of core ecological engineering sciences and curricula; and (3) certification in ecological design. These elements are important components of a formal approach to develop ecological engineering as a principled, quantitative, recognized, practical, novel, and formal engineering discipline that coalesces past and future research and practice into cohesive underpinnings.     

Cellular microbiology: Bacterial toxin interference drives understanding of eukaryotic cell function

Intimate interactions between the armament of pathogens and their host dictate tissue and host susceptibility to infection also forging specific pathophysiological outcomes. Studying these interactions at the molecular level has provided an invaluable source of knowledge on cellular processes, as ambitioned by the Cellular Microbiology discipline when it emerged in early 90s. Bacterial toxins act on key cell regulators or membranes to produce major diseases and therefore constitute a remarkable toolbox for dissecting basic biological processes. Here, we review selected examples of recent studies on bacterial toxins illustrating how fruitful the discipline of cellular microbiology is in shaping our understanding of eukaryote processes. This ever‐renewing discipline unveils new virulence factor biochemical activities shared by eukaryotic enzymes and hidden rules of cell proteome homeostasis, a particularly promising field to interrogate the impact of proteostasis breaching in late onset human diseases. It is integrating new concepts from the physics of soft matter to capture biomechanical determinants forging cells and tissues architecture. The success of this discipline is also grounded by the development of therapeutic tools and new strategies to treat both infectious and noncommunicable human diseases.     

The Anthropology of Authenticity: Everyman His Own Anthropologist

Anthropology, the contributors to the recent volume Reinventing Anthropology tell us, is suffering from severe hardening of the intellectual arteries. In order for it to be revitalized, they say, the discipline must be de-professionalized and de-institutionalized, made more personal and existential. This involves a rejection of the pose of "objectivity" and "value-free" inquiry and an open admission of the inherently ideological nature of the discipline. In a word, anthropology will have to become politically and morally partisan. This essay explores some of the implications of the recommendations made by the reinventors of anthropology. The stance taken in Reinventing Anthropology, this paper contends, would not only undermine anthropology as a systematic field of inquiry but would also negate whatever "relevance" the discipline might have to the contemporary world.     

A ligand-centric analysis of the diversity and evolution of protein-ligand relationships in E.coli

As enzymes evolve and diverge from common ancestor sequences, they often keep their overall reaction chemistry but specialize in the binding of different cognate ligands. This study borrows methods for the computational assessment of 2D similarity of small molecules from the field of chemoinformatics, to examine the extent of structure conservation of cognate ligands binding to similar proteins. Proteins from 87 structural superfamilies from Escherichia coli form the core dataset, which is extended using homologues with functional assignments from any organism. We find that correlation of the substrate similarity with protein similarity (measured by either sequence-based or structure-based scores) can only be clearly established for very similar proteins. At low sequence identities, the superfamily to which a protein belongs can give helpful clues to its function, and more importantly, the confidence attached to such clues is superfamily-dependent. Our data indicate that only a few superfamilies show great substrate diversity, and that most exhibit conservation of at least part of the structural scaffold of the substrate.     

旅游生态学研究体系

旅游生态学是一门新兴的应用性交叉学科,学科建立的时间短,学科体系发展有待完善.从学科体系研究入手,从学科的概念、研究领域、研究内容和研究方法等方面来探讨如何构建和完善旅游生态学研究体系.提出了旅游生态系统是旅游生态学研究的核心;旅游生态系统的组成、结构、功能和管理等是旅游生态学学科研究的主要支撑,是旅游生态学的重要研究内容;旅游野外研究方法、空间分析方法、旅游生态评价和旅游生态管理等方法为学科的主要研究方法.