[Molecular modeling and computer-aided drug design 1992-3--an overview].
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Computer-Aided Design↗
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Computer-assisted drug design: current status and future trends.
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Computer-Aided Design↗
Enzyme isoselective inhibitors: application to drug design.
Common methodologies of computer-assisted drug design focus on noncovalent enzyme-ligand interactions. We introduced enzyme isoselective inhibition trend analysis as a tool for the expert analysis of covalent reversible inhibitors. The methodology is applied to predict the binding affinities of a series of transition-state analogue inhibitors of medicinally important serine and cysteine hydrolases. These inhibitors are isoselective: they have identical noncovalent recognition fragments (RS) and different reactive chemical fragments (CS). Furthermore, it is possible to predict the binding affinities of a series of isoselective inhibitors toward a prototype enzyme and to extrapolate the data to a target medicinally important enzyme of the same family. Rational design of CS fragments followed by conventional RS optimization could be used as a novel approach to drug design.
Drug Design↗
Impact of recombinant DNA technology and protein engineering on structure-based drug design: case studies of HIV-1 and HCMV proteases.
Structure-based drug design is an organized, multidisciplinary endeavor undertaken by scientists from many different scientific fields. The success of structure-based drug design was only made possible by advances in structure biology that provides the three-dimensional structure of the drug design target with which small molecular chemical ligands interact. Visualization of the conformation and interactions of a small molecule ligand bound to the protein target in the co-crystal structure of the protein:ligand complex enables the design of new chemical compounds with improved binding affinity and specificity. With the advances in molecular biology, lab automation, and computational science, genomic data have now become available for the human genome, as well as various other organisms. The pharmaceutical industry is currently putting forth tremendous effort in the area of functional genomics and structural genomics in attempts to decipher functions and structures of protein encoded by genes, with the ultimate goal of identifying novel targets for drug discovery and development. This chapter discusses the significant impact made by recombinant DNA technology and protein engineering on structural biology and, more specifically, on structure-based drug design.
Biotechnology↗
Estimation of aqueous solubility in drug design.
The solubility of drugs in water is of central importance in the process of drug discovery and development from molecular design to pharmaceutical formulation and biopharmacy. The ability to estimate the aqueous solubility and other properties of a promising lead compound affecting its pharmacokinetics is a prerequisite to rational drug design, although it has received much less attention than the prediction of drug-receptor interactions. In this review, methods for the estimation of aqueous solubility of organic compounds are described and limited to approaches, which might be used in the early stage of drug design and development.
Chemical Phenomena↗
Silicon chemistry as a novel source of chemical diversity in drug design.
The use of organosilicon chemistry in drug design is reviewed. The field of bioorganosilicon chemistry, which sprung up in the 1970s to exploit the opportunities of silicon for drug design, is currently being developed into a practical and commercial enterprise. This review is mainly focused on two different approaches: (i) synthesizing a silicon analog of a known drug in which one carbon atom has been replaced by a silicon atom, with the rest of the molecule being identical (carbon/silicon switch, sila-substitution); (ii) synthesizing completely new silicon-based classes of compounds (the carbon analogs of which do not exist) that exploit specific features of silicon chemistry to address a well-validated target.
Amino Acids↗
The designer drug situation in Ibiza.
A total of 137 urine samples and 46 serum samples, corresponding to 154 self-confessed designer drugs consumers in Ibiza island, were analyzed for the presence of designer drugs: amphetamine and amphetamine derivatives (methamphetamine, methylenedioxymethamphetamine (MDMA), methylenedioxyethylamphetamine (MDEA), methylenedioxyamphetamine (MDA), p-methoxymethylamphetamine (PMMA), p-methoxyamphetamine (PMA), etc.), ketamine and gamma-hydroxybutyric acid. Among this population, coming both from the forensic clinic and from the emergency room of a hospital, a total of 99 cases were found positive for some designer drug. This study shows the prevalence of methylenedioxymethamphetamine (MDMA) among designer drug users, sole or in association with other drugs. Also, the mixture of MDMA with other designer drugs, ethanol and/or cocaine is shown to be more likely to produce toxic symptoms requiring clinical attendance in a hospital emergency room. These findings along with the consumption history, the concentrations of drugs and metabolites in urine and serum and the toxicological significance for the interpretation of some MDMA metabolites such as 4-hydroxy-3-methoxymethamphetamine (HMMA) are discussed in this study.
Designer Drugs↗
Evaluation of homology modeling of the severe acute respiratory syndrome (SARS) coronavirus main protease for structure based drug design.
To accelerate the development of drugs against severe acute respiratory syndrome (SARS), we constructed a homology model of the SARS coronavirus main protease using our modeling software, FAMS Ligand&Complex, and released it before the X-ray structure was solved. The X-ray structure showed our model as accurately predicted and useful for structure based drug design.
Antiviral Agents↗
Structure-aided drug design: crystallography and computational approaches.
Ideally, a drug that effectively attacks a specific target will be efficacious with few or no side effects. Historically, drug development has relied on a structure-activity sequential (trial-and-error) approach, testing many compounds and observing their pharmacologic effects. More recently, molecular biologists have investigated a new approach to drug design: starting with a specific target, determining what types of molecules would have a desired effect on that target and then constructing molecules that fit those criteria. Structure-aided drug design is a tool used in this new approach, which involves using crystallographic data and computer processing to describe a molecule precisely--in terms of all binding, Van der Waal's and electrostatic interactions--as a computational entity. The goal of this computational approach is to determine whether a molecule will bind to a target molecule and the character of the ligand interaction.
Computer Simulation↗
The impact of new technologies on drug design.
The Cutting Edge Approaches to Drug Design symposium, held March 13, 2001, in London, U.K., was organized by the Royal Society of Chemistry's Molecular Modelling Group and the Structural Biology Group of the Biochemical Society. The symposium was aimed primarily at medicinal chemists keen to discover how cutting edge methods can accelerate drug design. The talks were aimed at the nonspecialist, and topics included target finding, virtual screening, informatics in lead optimization and in silico pharmacokinetic profiling. Several examples demonstrated the power of these methods.
Journal Article↗
Update on computer-aided drug design.
Recent advances in computational methods for drug design include developments in quantitative structure-activity relationship approaches as well as novel structure-based strategies. Many new protein structures of pharmaceutical interest have been solved, a number of which contain a bound inhibitor. Continued progress has been reported in algorithms for de novo design, ligand docking, and scoring of protein-ligand binding energy. Meanwhile, several drugs that were designed by intensive use of computational methods are advancing through clinical trials.
Biotechnology↗
Omeprazole and talampanel as two examples of retrometabolic drug design.
The goal of retrometabolic drug design is: "to design safe, locally active compounds with an improved therapeutic index". Here we describe two cases from our own practice, talampanel and omeprazole.
Anticonvulsants↗
Perspectives in drug design against malaria.
Development of drug resistance by Plasmodium falciparum and insecticide resistance by the mosquito has lead to the resurgence of the most virulent forms of malaria. This review aims to provide a general perspective on drug design for P. falciparum malaria. Though numerous targets have been identified, new clinically useful target-specific inhibitors remain a distant prospect. This review focuses on pathways and enzymes for which some structural information and detailed biochemistry along with specificity of inhibitor action is available. Aspects of the parasite glycolytic pathway, nucleotide metabolism, proteases, redox metabolism and organelle function have been used to highlight possible targets and molecules that could inhibit their function.
Animals↗
Trypsin mutants for structure-based drug design: expression, refolding and crystallisation.
New techniques in drug discovery are essential for the fast and efficient development of novel innovative drugs to deal with the challenges of the future. Structure determinations of various members of serine proteinases have provided a basis for computer-based drug design within this class of enzymes. In many proteins of interest, however, this course is blocked through a lack of suitable crystals. As a strategy for circumventing such problems, we have investigated the use of surrogate proteins for studying protein-ligand interactions. To test the feasibility of this approach, we have chosen bovine trypsin as a scaffold to reconstruct the ligand binding site of factor Xa. The simple modular design of trypsin, its readiness to crystallise and straightforward handling lends itself to such drug design by proxy. The expression, folding, purification, crystallographic and kinetic characterisation of bovine trypsin forms with factor Xa phenotype are presented.
Animals↗
Computer aids in drug design--highlights.
An outline of some procedures used for computer aided drug design has been given. The emphasis is on lead generation, both primary and secondary, and on current lead optimization processes which rely on an appreciation of ligand-receptor interactions. The areas covered include techniques for structure based drug design and lead optimization, ligand-receptor interaction studies using molecular surfaces and docking, extraction of pharmacophore pattern to obtain new leads, expert system application etc.
Computer-Aided Design↗
Identification of monoamine oxidase and cytochrome P450 isoenzymes involved in the deamination of phenethylamine-derived designer drugs (2C-series).
In recent years, several compounds of the phenethylamine-type (2C-series) have entered the illicit drug market as designer drugs. In former studies, the qualitative metabolism of frequently abused 2Cs (2C-B, 2C-I, 2C-D, 2C-E, 2C-T-2, 2C-T-7) was studied using a rat model. Major phase I metabolic steps were deamination and O-demethylation. Deamination to the corresponding aldehyde was the reaction, which was observed for all studied compounds. Such reactions could in principal be catalyzed by two enzyme systems: monoamine oxidase (MAO) and cytochrome P450 (CYP). The aim of this study was to determine the human MAO and CYP isoenzymes involved in this major metabolic step and to measure the Michaelis-Menten kinetics of the deamination reactions. For these studies, cDNA-expressed CYPs and MAOs were used. The formation of the aldehyde metabolite was measured using GC-MS after extraction. For all compounds studied, MAO-A and MAO-B were the major enzymes involved in the deamination. For 2C-D, 2C-E, 2C-T-2 and 2C-T-7, CYP2D6 was also involved, but only to a very small extent. Because of the isoenzymes involved, the 2Cs are likely to be susceptible for drug-drug interactions with MAO inhibitors.
Cytochrome P-450 Enzyme System↗
Methods for the prediction of protein-ligand binding sites for structure-based drug design and virtual ligand screening.
Structure Based Drug Design (SBDD) is a computational approach to lead discovery that uses the three-dimensional structure of a protein to fit drug-like molecules into a ligand binding site to modulate function. Identifying the location of the binding site is therefore a vital first step in this process, restricting the search space for SBDD or virtual screening studies. The detection and characterisation of functional sites on proteins has increasingly become an area of interest. Structural genomics projects are increasingly yielding protein structures with unknown functions and binding sites. Binding site prediction was pioneered by pocket detection, since the binding site is often found in the largest pocket. More recent methods involve phylogenetic analysis, identifying structural similarity with proteins of known function and identifying regions on the protein surface with a potential for high binding affinity. Binding site prediction has been used in several SBDD projects and has been incorporated into several docking tools. We discuss different methods of ligand binding site prediction, their strengths and weaknesses, and how they have been used in SBDD.
Animals↗
New approaches to drug design and delivery based on drug-membrane interactions.
In this review, the complex physical and chemical interactions of drugs with model and biological membranes under normal and pathological conditions are examined at the molecular level. The results of our own published and unpublished structural studies are discussed and correlated with kinetic binding studies to assess the potential role of nonspecific drug interaction with the membrane bilayer in the overall receptor binding mechanism for membrane-bound receptors in heart and brain.
Algorithms↗