Home About us Contact
|
Home About us Contact | ||
|
|
||
Rational Drug Design (rational + drug_design)
Selected AbstractsHTS and Rational Drug Design to Generate a Class of 5-HT2C -Selective Ligands for Possible Use in Schizophrenia.CHEMMEDCHEM, Issue 8 2010Treating neurological conditions: Optimization of a previously identified lead 5-HT2C agonist (left) led to the discovery of a highly selective 5-HT2C agonist (right). Importantly, this compound is a 5-HT2B receptor antagonist. Because of its selective 5-HT2C receptor activity, the compound was further evaluated in the phencyclidine model of disrupted prepulse inhibition, and found to exhibit normalizing effects comparable to those shown by the 5-HT2C agonist vabicaserin, a drug currently in phase,II clinical studies for schizophrenia. [source] The structural comparison of the bacterial PepX and human DPP-IV reveals sites for the design of inhibitors of PepX activityFEBS JOURNAL, Issue 8 2005Pascal Rigolet X-prolyl dipeptidyl aminopeptidases (X-PDAP) are enzymes catalysing the release of dipeptides from the amino termini of polypeptides containing a proline or an alanine at the penultimate position. Involved in various mammalian regulation processes, as well as in chronic human diseases, they have been proposed to play a role in pathogenicity for Streptococci. We compared the structure of X-PDAP from Lactococcus lactis (PepX) with its human counterpart DPP-IV. Despite very different overall folds, the residues most implicated for X-PDAP activity are conserved in the same positions and orientations in both enzymes, thus defining a structural signature for the X-PDAP specificity that crosses the species frontiers of evolution. Starting from this observation, we tested some inhibitors of DPP-IV on PepX activity, for which no specific inhibitor is known. We thus found that PepX was highly sensitive to valine-pyrrolidide with a KI of 9.3 µm, close to that reported in DPP-IV inhibition. We finally used the structure of PepX from L. lactis as a template for computer-based homology modeling of PepX from the pathogenic Streptococcus gordonii. Docking simulations of valine-pyrrolidide into the active site of PepX led to the identification of key residues for a rational drug design against PepX from Streptococci. These results could have applications in human health giving new perspectives to the struggle against pathogens. [source] The expansion of mechanistic and organismic diversity associated with non-ribosomal peptidesFEMS MICROBIOLOGY LETTERS, Issue 2 2000Michelle C Moffitt Abstract Non-ribosomal peptides are a group of secondary metabolites with a wide range of bioactivities, produced by prokaryotes and lower eukaryotes. Recently, non-ribosomal synthesis has been detected in diverse microorganisms, including the myxobacteria and cyanobacteria. Peptides biosynthesized non-ribosomally may often play a primary or secondary role in the producing organism. Non-ribosomal peptides are often small in size and contain unusual or modified amino acids. Biosynthesis occurs via large modular enzyme complexes, with each module responsible for the activation and thiolation of each amino acid, followed by peptide bond formation between activated amino acids. Modules may also be responsible for the enzymatic modification of the substrate amino acid. Recent analysis of biosynthetic gene clusters has identified novel integrated, mixed and hybrid enzyme systems. These diverse mechanisms of biosynthesis result in the wide variety of non-ribosomal peptide structures and bioactivities seen today. Knowledge of these biosynthetic systems is rapidly increasing and methods of genetically engineering these systems are being developed. In the future, this may lead to rational drug design through combinatorial biosynthesis of these enzyme systems. [source] PDB_REDO: automated re-refinement of X-ray structure models in the PDBJOURNAL OF APPLIED CRYSTALLOGRAPHY, Issue 3 2009Robbie P. Joosten Structural biology, homology modelling and rational drug design require accurate three-dimensional macromolecular coordinates. However, the coordinates in the Protein Data Bank (PDB) have not all been obtained using the latest experimental and computational methods. In this study a method is presented for automated re-refinement of existing structure models in the PDB. A large-scale benchmark with 16,807 PDB entries showed that they can be improved in terms of fit to the deposited experimental X-ray data as well as in terms of geometric quality. The re-refinement protocol uses TLS models to describe concerted atom movement. The resulting structure models are made available through the PDB_REDO databank (http://www.cmbi.ru.nl/pdb_redo/). Grid computing techniques were used to overcome the computational requirements of this endeavour. [source] Molecular docking studies of selected tricyclic and quinone derivatives on trypanothione reductase of Leishmania infantumJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 13 2010Santhosh Kannan Venkatesan Abstract Visceral leishmaniasis, most lethal form of Leishmaniasis, is caused by Leishmania infantum in the Old world. Current therapeutics for the disease is associated with a risk of high toxicity and development of drug resistant strains. Thiol-redox metabolism involving trypanothione and trypanothione reductase, key for survival of Leishmania, is a validated target for rational drug design. Recently published structure of trypanothione reductase (TryR) from L. infantum, in oxidized and reduced form along with Sb(III), provides vital clues on active site of the enzyme. In continuation with our attempts to identify potent inhibitors of TryR, we have modeled binding modes of selected tricyclic compounds and quinone derivatives, using AutoDock4. Here, we report a unique binding mode for quinone derivatives and 9-aminoacridine derivatives, at the FAD binding domain. A conserved hydrogen bonding pattern was observed in all these compounds with residues Thr335, Lys60, His461. With the fact that these residues aid in the orientation of FAD towards the active site forming the core of the FAD binding domain, designing selective and potent compounds that could replace FAD in vivo during the synthesis of Trypanothione reductase can be deployed as an effective strategy in designing new drugs towards Leishmaniasis. We also report the binding of Phenothiazine and 9-aminoacridine derivatives at the Z site of the protein. The biological significance and possible mode of inhibition by quinone derivatives, which binds to FAD binding domain, along with other compounds are discussed. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010 [source] Information theoretical measures to analyze trajectories in rational molecular designJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 16 2007K. Hamacher Abstract We develop a new methodology to analyze molecular dynamics trajectories and other time series data from simulation runs. This methodology is based on an information measure of the difference between distributions of various data extract from such simulations. The method is fast as it only involves the numerical integration/summation of the distributions in one dimension while avoiding sampling issues at the same time. The method is most suitable for applications in which different scenarios are to be compared, e.g. to guide rational molecular design. We show the power of the proposed method in an application of rational drug design by reduced model computations on the BH3 motif in the apoptosis inducing BCL2 protein family. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2007 [source] A molecular dynamics study on binding recognition between several 4,5 and 4,6-linked aminoglycosides with A-site RNAJOURNAL OF MOLECULAR RECOGNITION, Issue 5 2010Shih-Yuan Chen Abstract A molecular dynamics (MD) simulation has been performed for two sets of aminoglycoside antibiotics bound with an RNA duplex corresponding to the aminoacyl-tRNA decoding site of the 16S rRNA to characterize the energetics and dynamics of binding for several aminoglycosides. The binding free energy, essential dynamics and hydration analysis have been conducted to characterize the dynamics' properties associated with the binding recognition between each set of antibiotics and the RNA duplex. We have built several dynamic models with reasonable binding free energies showing good correlation with the experimental data. We have also conducted a hydration analysis on some long residency water molecules detected as W8 and W49 sites around the U1406,·,U1495 pair and which are found to be important in binding recognition and in causing some apparent stretch variations of this pair during the dynamic studies. In addition, we also find that the hydration sites with long residence time identified between the ring III of two 4,6-linked antibiotics (tobramycin and kanamycin) and phosphate oxygen atoms of G1405/U1406 may be worthy of further exploration for rational drug design. Copyright © 2009 John Wiley & Sons, Ltd. [source] Expression of PPAR, RXR isoforms and fatty acid transporting proteins in the rat and human gastrointestinal tractsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 2 2005Q. Wang Abstract Dietary fatty acid (FA) absorption across the gastrointestinal (GI) tract is of critical importance for sustenance, however, excessive FA absorption has also been linked to metabolic syndrome and associated disorders. The expression of isoforms that regulate the dietary FA absorption are not as well characterized in the GI tract as they are elsewhere. Peroxisome proliferator-activated receptors (PPAR,, ,, and ,) and 9- cis -retinoic acid receptors (RXR,, ,, and ,) are nuclear hormone transcription factors that control FA homeostasis, in part through the regulation of expression of membrane-bound FA transporting proteins. The present study was designed to elucidate the expression of PPAR and RXR isoforms and FA transporting proteins (FABPpm and FAT/CD36) in the rat and human GI tracts using reverse transcriptase-polymerase chain reaction (RT-PCR), immunoblotting, and immunohistochemical staining. The results revealed rat GI expression of all the PPAR and RXR isoforms, FABPpm and FAT/CD36. PPAR,, PPAR,, PPAR,, RXR,, FABPpm, and FAT/CD36 isoforms exhibited ubiquitous expression in human GI tract, whereas RXR, was not detected. RXR, was observed in a majority of the human GI samples. These results provide a physiological foundation for rational drug design and drug delivery for the mitigation of metabolic syndrome and associated disorders to normalize intestinal FA absorption. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:363,372, 2005 [source] Towards a rational drug design: Raman micro-spectroscopy analysis of prostate cancer cells treated with an aqueous extract of Nerium OleanderJOURNAL OF RAMAN SPECTROSCOPY, Issue 11 2009A. Saha Abstract Raman spectroscopy is an efficient optical technique used to identify and grade cancer on the basis of the molecular composition of the cell. In this work Raman spectroscopy is used to study the chemical alteration occurring inside a prostate cancer cell as a result of a treatment with a low-concentration aqueous extract of Nerium Oleander. The results show that Nerium Oleander affects the protein and lipid concentration of cancer cells. Copyright © 2009 John Wiley & Sons, Ltd. [source] Hemostatic complications of angiogenesis inhibitors in cancer patients,AMERICAN JOURNAL OF HEMATOLOGY, Issue 11 2008Francesca Elice Tumor vasculature and tumor-associated neo-angiogenesis have recently become major targets for rational drug design of antineoplastic agents. Five such agents with angiogenesis inhibiting activity (thalidomide, lenalidomide, bevacizumab, sunitinib, sorafenib) have already obtained US Food and Drug Administration approval for clinical use and many others have entered clinical trials. Vascular complications, including venous or arterial thromboembolism and hemorrhage, have emerged as relevant toxicities in several clinical trials with angiogenesis inhibitors. Given the well-known interplay between the blood clotting system, angiogenesis, and tumor growth, a better understanding of the impact of these new drugs on overall hemostatic balance is required. In this brief overview, we discuss the incidence of hemostatic complications, the likely pathogenetic mechanisms involved, and the critical need to establish in randomized clinical trials the usefulness of thrombosis prophylaxis to prevent these complications. Careful documentation of hemostatic complications during treatment with each of the new antiangiogenic drugs is warranted. Further studies are urgently required to better define the causal association of these new agents with hemostatic complications and to establish the best prophylactic strategy. Am. J. Hematol., 2008. © 2008 Wiley-Liss, Inc. [source] Induced-fit or preexisting equilibrium dynamics?PROTEIN SCIENCE, Issue 4 2008Lessons from protein crystallography, MD simulations on acetylcholinesterase, implications for structure-based drug design Abstract Crystal structures of acetylcholinesterase complexed with ligands are compared with side-chain conformations accessed by native acetylcholinesterase in molecular dynamics (MD) simulations. Several crystallographic conformations of a key residue in a specific binding site are accessed in a simulation of native acetylcholinesterase, although not seen in rotomer plots. Conformational changes upon ligand binding thus involve preexisting equilibrium dynamics. Consequently, rational drug design could benefit significantly from conformations monitored by MD simulations of native targets. [source] Topography of a 2.0 Å structure of ,1 -antitrypsin reveals targets for rational drug design to prevent conformational diseasePROTEIN SCIENCE, Issue 7 2000Peter R. Elliott Abstract Members of the serpin family of serine proteinase inhibitors play important roles in the inflammatory, coagulation, fibrinolytic, and complement cascades. An inherent part of their function is the ability to undergo a structural rearrangement, the stressed (S) to relaxed (R) transition, in which an extra strand is inserted into the central A ,-sheet. In order for this transition to take place, the A sheet has to be unusually flexible. Malfunctions in this flexibility can lead to aberrant protein linkage, serpin inactivation, and diseases as diverse as cirrhosis, thrombosis, angioedema, emphysema, and dementia. The development of agents that control this conformational rearrangement requires a high resolution structure of an active serpin. We present here the topology of the archetypal serpin ,1 -antitrypsin to 2 Å resolution. This structure allows us to define five cavities that are potential targets for rational drug design to develop agents that will prevent conformational transitions and ameliorate the associated disease. [source] The human ACC2 CT-domain C-terminus is required for full functionality and has a novel twistACTA CRYSTALLOGRAPHICA SECTION D, Issue 5 2009Kevin P. Madauss Inhibition of acetyl-CoA carboxylase (ACC) may prevent lipid-induced insulin resistance and type 2 diabetes, making the enzyme an attractive pharmaceutical target. Although the enzyme is highly conserved amongst animals, only the yeast enzyme structure is available for rational drug design. The use of biophysical assays has permitted the identification of a specific C-terminal truncation of the 826-residue human ACC2 carboxyl transferase (CT) domain that is both functionally competent to bind inhibitors and crystallizes in their presence. This C-terminal truncation led to the determination of the human ACC2 CT domain,CP-640186 complex crystal structure, which revealed distinctions from the yeast-enzyme complex. The human ACC2 CT-domain C-terminus is comprised of three intertwined ,-helices that extend outwards from the enzyme on the opposite side to the ligand-binding site. Differences in the observed inhibitor conformation between the yeast and human structures are caused by differing residues in the binding pocket. [source] Structure of mouse IP-10, a chemokineACTA CRYSTALLOGRAPHICA SECTION D, Issue 6 2008Talat Jabeen Interferon-,-inducible protein (IP-10) belongs to the CXC class of chemokines and plays a significant role in the pathophysiology of various immune and inflammatory responses. It is also a potent angiostatic factor with antifibrotic properties. The biological activities of IP-10 are exerted by interactions with the G-protein-coupled receptor CXCR3 expressed on Th1 lymphocytes. IP-10 thus forms an attractive target for structure-based rational drug design of anti-inflammatory molecules. The crystal structure of mouse IP-10 has been determined and reveals a novel tetrameric association. In the tetramer, two conventional CXC chemokine dimers are associated through their N-terminal regions to form a 12-stranded elongated ,-sheet of ,90,Å in length. This association differs significantly from the previously studied tetramers of human IP-10, platelet factor 4 and neutrophil-activating peptide-2. In addition, heparin- and receptor-binding residues were mapped on the surface of IP-10 tetramer. Two heparin-binding sites were observed on the surface and were present at the interface of each of the two ,-sheet dimers. The structure supports the formation of higher order oligomers of IP-10, as observed in recent in vivo studies with mouse IP-10, which will have functional relevance. [source] Protein preparation, crystallization and preliminary X-ray analysis of Trypanosoma cruzi nucleoside diphosphate kinase 1ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 7 2010J. A. Gómez Barroso The flagellated protozoan parasite Trypanosoma cruzi is the aetiological agent of Chagas disease. Nucleoside diphosphate kinases (NDPKs) are enzymes that are involved in energy management and nucleoside balance in the cell. T. cruzi TcNDPK1, a canonical isoform, was overexpressed in Escherichia coli as an N-terminally poly-His-tagged fusion protein and crystallized. Crystals grew after 72,h in 0.2,M MgCl2, 20% PEG 3350. Data were collected to 3.5,Å resolution using synchrotron X-ray radiation at the National Synchrotron Light Laboratory (Campinas, Brazil). The crystals belonged to the trigonal space group P3, with unit-cell parameters a = b = 127.84, c = 275.49,Å. Structure determination is under way and will provide relevant information that may lead to the first step in rational drug design for the treatment of Chagas disease. [source] Peptidic modulators of protein-protein interactions: Progress and challenges in computational designBIOPOLYMERS, Issue 7 2009Mor Rubinstein Abstract With the decline in productivity of drug-development efforts, novel approaches to rational drug design are being introduced and developed. Naturally occurring and synthetic peptides are emerging as novel promising compounds that can specifically and efficiently modulate signaling pathways in vitro and in vivo. We describe sequence-based approaches that use peptides to mimic proteins in order to inhibit the interaction of the mimicked protein with its partners. We then discuss a structure-based approach, in which protein-peptide complex structures are used to rationally design and optimize peptidic inhibitors. We survey flexible peptide docking techniques and discuss current challenges and future directions in the rational design of peptidic inhibitors. © 2009 Wiley Periodicals, Inc. Biopolymers 91: 505,513, 2009. This article was originally published online as an accepted preprint. The "Published Online"date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com [source] Purification, crystallization and preliminary X-ray diffraction analysis of the CBS-domain pair from the Methanococcus jannaschii protein MJ0100ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 10 2008María Lucas CBS domains are small protein motifs consisting of a three-stranded ,-sheet and two ,-helices that are present in proteins of all kingdoms of life and in proteins with completely different functions. Several genetic diseases in humans have been associated with mutations in their sequence, which has made them promising targets for rational drug design. The C-terminal domain of the Methanococcus jannaschii protein MJ0100 includes a CBS-domain pair and has been overexpressed, purified and crystallized. Crystals of selenomethionine-substituted (SeMet) protein were also grown. The space group of both the native and SeMet crystals was determined to be orthorhombic P212121, with unit-cell parameters a = 80.9, b = 119.5, c = 173.3,Å. Preliminary analysis of the X-ray data indicated that there were eight molecules per asymmetric unit in both cases. [source] Design of Potent IGF1-R Inhibitors Related to Bis-azaindolesCHEMICAL BIOLOGY & DRUG DESIGN, Issue 2 2010Conception Nemecek From an azaindole lead, identified in high throughput screen, a series of potent bis-azaindole inhibitors of IGF1-R have been synthesized using rational drug design and SAR based on a in silico binding mode hypothesis. Although the resulting compounds produced the expected improved potency, the model was not validated by the co-crystallization experiments with IGF1-R. [source] Anatomical characterisation of voltage gated sodium channels in the mammalian cochlear nerve spiral gangliaCLINICAL OTOLARYNGOLOGY, Issue 6 2006A. Prasai Introduction., There is evidence that Voltage Gated Sodium Channels (VGSC) may represent novel therapeutic targets for treatment of certain types of tinnitus and hearing loss. It is also known that the different VGSC types vary in their affinity for differing VGSC blockers. Parallels have been drawn with certain types of tinnitus, chronic pain and epilepsy (1) These conditions are thought to arise from pathological VGSC activity (2) There has also been empirical interest in the use of VGSC blockers as tinnitolytics, with the best known of these being intravenous lignocaine. Aim., The aim of this study was first begin to characterise VGSCs in the mammalian cochlear nerve spiral ganglion. Method., After sacrifice, guinea pigs were perfused with heparin and then 2% paraformaldehyde. The bony matrix of the cochleae was decalcified in buffer containing EGTA (8%). Decalcified tissues were embedded; frozen and 20-micron cryosections were made through the cochleae. Immunocytochemistry was then carried out using antibodies that selectively bind to individual sodium channel ,-subunits. Sections were then analysed and photographed using either an epifluorescence or a confocal microscope. Results and Conclusions., Sodium channel type 1.6 and 1.7 were shown to be expressed in the cochlear nerve spiral ganglion. Further work is being carried out to see if there are changes in the expression of these VGSC after ototrauma. These findings may help us to target our therapy to treat certain types of tinnitus and hearing loss. References 1 Smith P.F., Darlington C.L. (2005) Drug treatments for subjective tinnitus: serendipitous discovery versus rational drug design. Curr. Opin. Investig. Drugs.6, 712,716 2 Taylor C.P., Meldrum B.S. (1995) Na+ channels as targets for neuroprotective drugs. Trends. Pharmacol. Sci. 16, 309,315 [source] | ||||||||||||||||||||||||||||