Design Of New Medicines Research Articles

Chemistry towards Biology-Instruct: Snapshot.

The knowledge of interactions between different molecules is undoubtedly the driving force of all contemporary biomedical and biological sciences. Chemical biology/biological chemistry has become an important multidisciplinary bridge connecting the perspectives of chemistry and biology to the study of small molecules/peptidomimetics and their interactions in biological systems. Advances in structural biology research, in particular linking atomic structure to molecular properties and cellular context, are essential for the sophisticated design of new medicines that exhibit a high degree of druggability and very importantly, druglikeness. The authors of this contribution are outstanding scientists in the field who provided a brief overview of their work, which is arranged from in silico investigation through the characterization of interactions of compounds with biomolecules to bioactive materials.

Formation, Development, and Cross-Species Interactions in Biofilms.

Biofilms, which are essential vectors of bacterial survival, protect microbes from antibiotics and host immune attack and are one of the leading causes that maintain drug-resistant chronic infections. In nature, compared with monomicrobial biofilms, polymicrobial biofilms composed of multispecies bacteria predominate, which means that it is significant to explore the interactions between microorganisms from different kingdoms, species, and strains. Cross-microbial interactions exist during biofilm development, either synergistically or antagonistically. Although research into cross-species biofilms remains at an early stage, in this review, the important mechanisms that are involved in biofilm formation are delineated. Then, recent studies that investigated cross-species cooperation or synergy, competition or antagonism in biofilms, and various components that mediate those interactions will be elaborated. To determine approaches that minimize the harmful effects of biofilms, it is important to understand the interactions between microbial species. The knowledge gained from these investigations has the potential to guide studies into microbial sociality in natural settings and to help in the design of new medicines and therapies to treat bacterial infections.

TolCV1 Has Multifaceted Roles During Vibrio vulnificus Infection.

RtxA1 is a major cytotoxin of Vibrio vulnificus (V. vulnificus) causing fatal septicemia and necrotic wound infections. Our previous work has shown that RpoS regulates the expression and secretion of V. vulnificus RtxA1 toxin. This study was conducted to further investigate the potential mechanisms of RpoS on RtxA1 secretion. First, V. vulnificus TolCV1 and TolCV2 proteins, two Escherichia coli TolC homologs, were measured at various time points by Western blotting. The expression of TolCV1 was increased time-dependently, whereas that of TolCV2 was decreased. Expression of both TolCV1 and TolCV2 was significantly downregulated in an rpoS deletion mutation. Subsequently, we explored the roles of TolCV1 and TolCV2 in V. vulnificus pathogenesis. Western blot analysis showed that RtxA1 toxin was exported by TolCV1, not TolCV2, which was consistent with the cytotoxicity results. Furthermore, the expression of TolCV1 and TolCV2 was increased after treatment of the host signal bile salt and the growth of tolCV1 mutant was totally abolished in the presence of bile salt. A tolCV1 mutation resulted in significant reduction of V. vulnificus induced-virulence in mice. Taken together, TolCV1 plays key roles in RtxA1 secretion, bile salt resistance, and mice lethality of V. vulnificus, suggesting that TolCV1 could be an attractive target for the design of new medicines to treat V. vulnificus infections.

Genomics, Computational Biology and Drug Discovery for Mycobacterial Infections: Fighting the Emergence of Resistance.

Tuberculosis (TB) and leprosy are mycobacterial infections caused by Mycobacterium tuberculosis and Mycobacterium leprae respectively. These diseases continue to be endemic in developing countries where the cost of new medicines presents major challenges. The situation is further exacerbated by the emergence of resistance to many front-line antibiotics. A priority now is to design new antimycobacterials that are not only effective in combatting the diseases but are also less likely to give rise to resistance. In both these respects understanding the structure of drug targets in M. tuberculosis and M. leprae is crucial. In this review we describe structure-guided approaches to understanding the impacts of mutations that give rise to antimycobacterial resistance and the use of this information in the design of new medicines.

Conceptual DFT as a Novel Chemoinformatics Tool for Studying the Chemical Reactivity Properties of the Amatoxin Family of Fungal Peptides

AbstractThe chemical structures and molecular reactivities of the Amatoxin group of fungi-derived peptides have been determined by means of the consideration of a model chemistry that has been previously validated as well-behaved for our purposes. The reactivity descriptors were calculated on the basis of a methodological framework built around the concepts that are the outcome of the so called Conceptual Density Functional Theory (CDFT). This procedure in connection with the different Fukui functions allowed to identify the chemically active regions within the molecules. By considering a simple protocol designed by our research group for the estimation of the pKa of peptides through the information coming from the chemical hardness, these property has been established for the different molecular systems explored in this research. The information reported through this work could be of interest for medicinal chemistry researchers in using this knowledge for the design of new medicines based on the studied peptides or as a help for the understanding of the toxicity mechanisms exerted by them.

Bacterial Quorum Sensing and Microbial Community Interactions.

ABSTRACTMany bacteria use a cell-cell communication system called quorum sensing to coordinate population density-dependent changes in behavior. Quorum sensing involves production of and response to diffusible or secreted signals, which can vary substantially across different types of bacteria. In many species, quorum sensing modulates virulence functions and is important for pathogenesis. Over the past half-century, there has been a significant accumulation of knowledge of the molecular mechanisms, signal structures, gene regulons, and behavioral responses associated with quorum-sensing systems in diverse bacteria. More recent studies have focused on understanding quorum sensing in the context of bacterial sociality. Studies of the role of quorum sensing in cooperative and competitive microbial interactions have revealed how quorum sensing coordinates interactions both within a species and between species. Such studies of quorum sensing as a social behavior have relied on the development of “synthetic ecological” models that use nonclonal bacterial populations. In this review, we discuss some of these models and recent advances in understanding how microbes might interact with one another using quorum sensing. The knowledge gained from these lines of investigation has the potential to guide studies of microbial sociality in natural settings and the design of new medicines and therapies to treat bacterial infections.

大数据与化学数据挖掘

Big data is fast becoming an important resource and a hot topic in academic research, business and government. In this paper, we introduce the concept of big data, and review advances in big data research, including technology for big data collection, cloud computing technology like Googles file system, BigTable, MapReduce and Hadoop, and data mining and visualization methods for big data. Big data are commonly defined by the so-called 4 Vs, i.e., volume, variety, velocity, and value. High volume data with large variety make the analysis of big data much more difficult. Since velocity is important, fast high performance analysis methods are needed for big data. Moreover, the high value of big data is precisely the reason for the importance of and research activity in this area. In this paper, we also summarize various applications of big data in chemistry. Professional information platforms like the Collaboratory for Multi-scale Chemical Sciences (CMCS) and Chemical Informatics and Cyberinfrastructure Collaboratory (CICC) have been developed to manage and research chemical big data, while search engines like the ChemDB Portal have been established to extract chemical information from the internet. Software like the Integrated Project View and ArQiologist can be used to assist in the design of new medicines in medicinal chemistry. A data management system called BioGames has been proposed to analyze microfluidics big data. Moreover, graphics processing units are widely used to improve the computational capabilities of molecular dynamics simulations, while compressed score plots have been proposed to solve visualization issues in the field of chemometrics. In the era of big data, the analytical instruments, chemical data systems, and even the research methods may need to be changed and therefore, new strategies and techniques are still needed for the generation and processing of big data.

Biosafe nanoscale pharmaceutical adjuvant materials.

Thanks to developments in the field of nanotechnology over the past decades, more and more biosafe nanoscale materials have become available for use as pharmaceutical adjuvants in medical research. Nanomaterials possess unique properties which could be employed to develop drug carriers with longer circulation time, higher loading capacity, better stability in physiological conditions, controlled drug release, and targeted drug delivery. In this review article, we will review recent progress in the application of representative organic, inorganic and hybrid biosafe nanoscale materials in pharmaceutical research, especially focusing on nanomaterial-based novel drug delivery systems. In addition, we briefly discuss the advantages and notable functions that make these nanomaterials suitable for the design of new medicines; the biosafety of each material discussed in this article is also highlighted to provide a comprehensive understanding of their adjuvant attributes.

Crystallography and Geopolitics

Developed and developing nations recognize that innovation is key to their economies. Connecting this with the discipline of crystallography may not seem immediately apparent, but during the past century, understanding the structure of matter has transformed industries and created new frontiers, from the design of new medicines and materials to assessing the mineral content of Mars. The future global economy will be determined by progress in cutting-edge fields. However, the playing field is not level in crystallography, which is why the International Union of Crystallography (IUCr) and the United Nations Educational, Scientific and Cultural Organization (UNESCO) have marked 2014 as the International Year of Crystallography. The aim is to improve public awareness of the field, boost access to instrumentation and high-level research, nurture “home-grown” crystallographers in developing nations, and increase international collaborations for the benefit of future generations.

Protein Conformational Populations and Functionally Relevant Substates

Functioning proteins do not remain fixed in a unique structure, but instead they sample a range of conformations facilitated by motions within the protein. Even in the native state, a protein exists as a collection of interconverting conformations driven by thermodynamic fluctuations. Motions on the fast time scale allow a protein to sample conformations in the nearby area of its conformational landscape, while motions on slower time scales give it access to conformations in distal areas of the landscape. Emerging evidence indicates that protein landscapes contain conformational substates with dynamic and structural features that support the designated function of the protein. Nuclear magnetic resonance (NMR) experiments provide information about conformational ensembles of proteins. X-ray crystallography allows researchers to identify the most populated states along the landscape, and computational simulations give atom-level information about the conformational substates of different proteins. This ability to characterize and obtain quantitative information about the conformational substates and the populations of proteins within them is allowing researchers to better understand the relationship between protein structure and dynamics and the mechanisms of protein function. In this Account, we discuss recent developments and challenges in the characterization of functionally relevant conformational populations and substates of proteins. In some enzymes, the sampling of functionally relevant conformational substates is connected to promoting the overall mechanism of catalysis. For example, the conformational landscape of the enzyme dihydrofolate reductase has multiple substates, which facilitate the binding and the release of the cofactor and substrate and catalyze the hydride transfer. For the enzyme cyclophilin A, computational simulations reveal that the long time scale conformational fluctuations enable the enzyme to access conformational substates that allow it to attain the transition state, therefore promoting the reaction mechanism. In the long term, this emerging view of proteins with conformational substates has broad implications for improving our understanding of enzymes, enzyme engineering, and better drug design. Researchers have already used photoactivation to modulate protein conformations as a strategy to develop a hypercatalytic enzyme. In addition, the alteration of the conformational substates through binding of ligands at locations other than the active site provides the basis for the design of new medicines through allosteric modulation.

Receptor-Based Computational Screening of Compound Databases: The Main Docking-Scoring Engines

The processes used by academic and industrial scientists to discover new drugs have recently experienced a true renaissance with many new and exciting techniques. The number of protein structures and/or chemical ligands is constantly growing, through the use of parallel chemistry, X-ray crystallography, NMR or homology modeling methods and so is the theoretical understanding of protein-ligand interactions. As such, structure-based approaches to drug-design and in silico screening are becoming routine part of most modern lead discovery programs. Prioritization of compound libraries is an extremely important task that aims at the rapid identification of tight-binding ligands and ultimately new therapeutic compounds. These in silico approaches combined with other experimental methods facilitate the design of new medicines to treat cardiovascular, degenerative, infectious, and neoplastic diseases, among others. Here, we review key concepts and specific features of several selected ligand-receptor docking/scoring methods while several other topics pertaining to the field of in silico screening are reviewed in the following articles of this special issue of Current Protein and Peptide Science.

Cloud-point temperature and liquid–liquid phase separation of supersaturated lysozyme solution

The detailed understanding of the structure of biological macromolecules reveals their functions, and is thus important in the design of new medicines and for engineering molecules with improved properties for industrial applications. Although techniques used for protein crystallization have been progressing greatly, protein crystallization may still be considered an art rather than a science, and successful crystallization remains largely empirical and operator-dependent. In this work, a microcalorimetric technique has been utilized to investigate liquid–liquid phase separation through measuring cloud-point temperature T cloud for supersaturated lysozyme solution. The effects of ionic strength and glycerol on the cloud-point temperature are studied in detail. Over the entire range of salt concentrations studied, the cloud-point temperature increases monotonically with the concentration of sodium chloride. When glycerol is added as additive, the solubility of lysozyme is increased, whereas the cloud-point temperature is decreased.

Phase transitions in lysozyme solutions characterized by differential scanning calorimetry

The detailed understanding of the structure of biological macromolecules reveals their functions and is thus important in the design of new medicines and for engineering molecules with improved properties for industrial applications. However, obtaining high-quality crystals of proteins for determining structures is still quite difficult in general, and successful protein crystallization remains largely empirical and operator-dependent. In this work, a microcalorimetric technique has been utilized to investigate liquid-liquid phase separation through measuring the cloud-point temperature T cloud for high supersaturated lysozyme solution, and the structure formation of lysozyme solution at low concentration. Pronounced heat-flow curves dependent on solution conditions during cooling process have been obtained and analyzed. The implications of calorimetric results are (i) as to lysozyme solution at low concentration, aggregates form and grow into clusters with the increase of supersaturation in the absence of glycerol, while three-dimensional network instead of aggregates maybe form in the presence of glycerol; (ii) with respect to concentrated lysozyme solution, the cloud-point temperature increases monotonically with the concentration of sodium chloride, and is decresed when glycerol is added as additive.

Application of structural biology tools in the study of viral hepatitis and the design of antiviral therapy

GASTROENTEROLOGY 2002;123:1350-1363

Recent advances in methodology for the crystallization of biological macromolecules

The detailed understanding of the structure of biological macromolecules reveals their function and is thus important in the design of new medicines and for engineering molecules with improved properties for industrial applications. X-ray diffraction is the most reliable method to determine the structure of such large molecules, but it can only be applied provided suitable crystals are obtained. The major bottleneck to structure determination is the ability to produce diffraction-quality crystals. This paper presents an approach which employs the use of oil as a major element in crystallization, and highlights recent oil-based technologies for producing crystals of biological macromolecules as well as techniques for controlling the nucleation and growth rates of the crystallization process.