ABSTRACT
Among natural metalloenzymes, the facial two-histidines one-carboxylate binding motif (FTM) is a widely represented first coordination sphere motif present in the active site of a variety of metalloenzymes. A PDB search revealed a total of 1685 structures bearing such FTMs bound to a metal. Sixty statistically representative FTMs were selected and used as template for the identification of structurally characterized proteins bearing these three amino acids in a propitious environment for binding to a transition metal. This geometrical superposition search, carried out using the STAMPS software, returned 2320 hits. While most consisted of either apo-FTMs or bore strong sequence homology to known FTMs, seven such structures lying within a cavity were identified as novel and viable scaffolds for the creation of artificial metalloenzymes bearing an FTM.
Subject(s)
Carboxylic Acids/chemistry , Histidine/chemistry , Metalloproteins/chemistry , Metals/chemistry , Amino Acid Motifs/genetics , Amino Acid Sequence , Binding Sites/genetics , Carboxylic Acids/metabolism , Carboxypeptidases A/chemistry , Carboxypeptidases A/metabolism , Computational Biology/methods , Databases, Protein , Histidine/genetics , Histidine/metabolism , Metalloproteins/genetics , Metalloproteins/metabolism , Metals/metabolism , Models, Molecular , Molecular Structure , Protein Conformation , Protein Structure, Tertiary , SoftwareABSTRACT
This editorial looks at how a fully integrated structure that performs all aspects in the drug discovery process, under one company, is slowly disappearing. The steps in the drug discovery paradigm have been slowly increasing toward virtuality or outsourcing at various phases of product development in a company's candidate pipeline. Each step in the process, such as target identification and validation and medicinal chemistry, can be managed by scientific teams within a 'virtual' company. Pharmaceutical companies to biotechnology start-ups have been quick in adopting this new research and development business strategy in order to gain flexibility, access the best technologies and technical expertise, and decrease product developmental costs. In today's financial climate, the term virtual drug discovery has an organizational meaning. It represents the next evolutionary step in outsourcing drug development.
ABSTRACT
We discuss thoroughly aspects and issues for the development of a bespoke, but generic, electronic infrastructure designed to cope with the dynamic in high-throughput experimentation and knowledge management, is applicable to large or contract research organizations. We present the first generation of an informatics platform developed for TOPCOMBI, a research project funded by the European Commission for Nanotechnology and Nanoscience. It is composed by an infrastructure and a collection of modules dealing with laboratory analytics, robotics, data handling and analytics, optimization, in-database processing and visualization, which are developed collegially by the partners of the Consortium. This best-of-breed informatics system enables the capture and the re-usage of processes and methodologies, i.e. process and data flows, using the workflow paradigm. Complex workflows designed by power users can be eventually used by either other domain experts or by novices through a web portal. Workflows can also be run interactively to allow visual analytics for instance, or automatically. We present two case studies dealing with the kinetic study of glycerol catalytic oxidation using parallel equipments, and a novel, fully integrated QSAR applied in heterogeneous catalysis, respectively.
Subject(s)
Computational Biology/methods , Catalysis , Glycerol/chemistry , Kinetics , Models, Chemical , Molecular Structure , Oxidation-Reduction , Quantitative Structure-Activity RelationshipABSTRACT
We report on the generation of artificial metalloenzymes based on the noncovalent incorporation of biotinylated rhodium-diphosphine complexes in (strept)avidin as host proteins. A chemogenetic optimization procedure allows one to optimize the enantioselectivity for the reduction of acetamidoacrylic acid (up to 96% ee (R) in streptavidin S112G and up to 80% ee (S) in WT avidin). The association constant between a prototypical cationic biotinylated rhodium-diphosphine catalyst precursor and the host proteins was determined at neutral pH: log K(a) = 7.7 for avidin (pI = 10.4) and log K(a) = 7.1 for streptavidin (pI = 6.4). It is shown that the optimal operating conditions for the enantioselective reduction are 5 bar at 30 degrees C with a 1% catalyst loading.
Subject(s)
Avidin/analogs & derivatives , Enzymes/chemistry , Metalloproteins/chemistry , Phosphines/chemistry , Rhodium/chemistry , Streptavidin/analogs & derivatives , Acrylates/chemistry , Avidin/biosynthesis , Avidin/chemistry , Avidin/genetics , Bacillus subtilis/genetics , Bacillus subtilis/metabolism , Biotin/analogs & derivatives , Biotin/chemistry , Catalysis , Enzymes/chemical synthesis , Hydrogenation , Kinetics , Metalloproteins/chemical synthesis , Models, Molecular , Mutagenesis, Site-Directed , Stereoisomerism , Streptavidin/biosynthesis , Streptavidin/chemistry , Streptavidin/geneticsABSTRACT
In this paper we propose a novel graph-based genetic algorithm for the evolution of novel molecular graphs from a predefined set of elements or molecular fragments with an external objective function. A brief overview of existing genetic algorithm approaches in molecular design is provided followed by a description of our approach. The paper continues to suggest a novel application of this program to the multiobjective evolution of median molecules that are structurally representative of a set of objective molecules. We conclude with a summary of our initial results along with a discussion of a variety of improvements and applications of our approach.
