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Results for “In silico screening”

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At least 127 records · Page 7Linked to original sources

PubMed2006

Role of the universal stress protein UspA of Salmonella in growth arrest, stress and virulence.

Pathogenic bacteria employ a variety of mechanisms to resist a barrage of stresses they encounter during active growth in or outside the host as well as during growth stasis. An in silico screen of the Salmonella genome sequence revealed that Salmonella typhimurium LT2 possesses a homologue belonging to the universal stress protein A (UspA) family. We assessed the transcriptional profile of uspA in S. typhimurium C5 by constructing a lacZ fusion revealing that uspA is induced by metabolic, oxidative, and temperature stresses. The highest transcriptional levels occurred in cells entering stationary phase, an observation consistent with expression patterns in Escherichia coli. The protein was purified as a fusion with GST (UspA(F)) and antibodies raised against UspA(F) revealed elevated protein levels in stressed and growth-arrested cells. Inactivation of uspA in S. typhimurium C5, lead to increased susceptibility to stress conditions. Furthermore, UspA makes an important contribution to the in vivo virulence of Salmonella in mice thus highlighting the importance of stress resistance regulation in pathogenicity and survival within the host.

Animals↗

PubMed2005

Establishment of robust functional assays for the characterization of neuropeptide Y (NPY) receptors: identification of 3-(5-benzoyl-thiazol-2-ylamino)-benzonitrile as selective NPY type 5 receptor antagonist.

The human Neuropeptide Y (NPY) receptors 1 (hY1), 2 (hY2), 4 (hY4), and the mouse type 5 (mY5) receptor were expressed in human embryonic kidney 293 (HEK293) cells. The receptors bound a radioiodinated NPY ligand with high affinity and various NPY analogs competed for binding in a receptor selective-manner. Similarly, cAMP-inhibition and GTPgammaS binding assays were established. The four NPY receptors were further tested in the fluorimetric imaging plate reader (FLIPR) format, a cellular high-throughput assay, in the absence and presence of chimeric G proteins, Gqo5, Gqi5 and Gqi9. The receptors stimulated transient calcium release only in the presence of chimeric G proteins. While hY1, hY2 and hY4 receptors coupled to Gqo5, Gqi5 and Gqi9, the mY5 receptor stimulated transient calcium release only when co-expressed with Gqi9. Using an in silico screening approach we identified a small molecule 3-(5-benzoyl-thiazol-2-ylamino)-benzonitrile (compound 1), which bound to the mY5 receptor with high affinity (Ki=32.1+/-1.8 nM), competitively antagonized NPY-mediated GTPgammaS binding and calcium stimulation with high potency, and had no affinity for other NPY receptors. These data show that NPY receptors can be functionally coupled to the FLIPR readout, allowing for high throughput compound testing and identification of novel molecules.

Animals↗

PubMed2006

Mining the oocyte transcriptome.

Mammalian folliculogenesis and oocyte physiology are complex and not fully understood. However, major advances over the past 15 years in our ability to create and study in vivo models have improved our understanding of these essential physiological processes. More recently, the availability of vast arrays of DNA sequence information in the forms of "complete" genomes, expressed sequence tag libraries and microarray data from reproductive tissues have stimulated the discovery of new information through genome scanning, prediction programs and in silico screening techniques. These technological improvements will help to expand our understanding of folliculogenesis and oocyte physiology and improve human reproductive health.

Bone Morphogenetic Protein 15↗

PubMed2006

Translational control genes in the sea urchin genome.

Sea urchin eggs and early cleavage stage embryos provide an example of regulated gene expression at the level of translation. The availability of the sea urchin genome offers the opportunity to investigate the "translational control" toolkit of this model system. The annotation of the genome reveals that most of the factors implicated in translational control are encoded by nonredundant genes in echinoderm, an advantage for future functional studies. In this paper, we focus on translation factors that have been shown or suggested to play crucial role in cell cycle and development of sea urchin embryos. Addressing the cap-binding translational control, three closely related eIF4E genes (class I, II, III) are present, whereas its repressor 4E-BP and its activator eIF4G are both encoded by one gene. Analysis of the class III eIF4E proteins in various phyla shows an echinoderm-specific amino acid substitution. Furthermore, an interaction site between eIF4G and poly(A)-binding protein is uncovered in the sea urchin eIF4G proteins and is conserved in metazoan evolution. In silico screening of the sea urchin genome has uncovered potential new regulators of eIF4E sharing the common eIF4E recognition motif. Taking together, these data provide new insights regarding the strong requirement of cap-dependent translation following fertilization. The genome analysis gives insights on the complexity of eEF1B structure and motifs of functional relevance, involved in the translational control of gene expression at the level of elongation. Finally, because deregulation of translation process can lead to diseases and tumor formation in humans, the sea urchin orthologs of human genes implicated in human diseases and signaling pathways regulating translation were also discussed.

Amino Acid Sequence↗

PubMed2001

Discovery of a new inhibitor lead of adenovirus proteinase: steps toward selective, irreversible inhibitors of cysteine proteinases.

Using the computer docking program EUDOC, in silico screening of a chemical database for inhibitors of human adenovirus cysteine proteinase (hAVCP) identified 2,4,5,7-tetranitro-9-fluorenone that selectively and irreversibly inhibits hAVCP in a two-step reaction: reversible binding (Ki = 3.09 microM) followed by irreversible inhibition (ki = 0.006 s(-1)). The reversible binding is due to molecular complementarity between the inhibitor and the active site of hAVCP, which confers the selectivity of the inhibitor. The irreversible inhibition is due to substitution of a nitro group of the inhibitor by the nearby Cys122 in the active site of hAVCP. These findings suggest a new approach to selective, irreversible inhibitors of cysteine proteinases involved in normal and abnormal physiological processes ranging from embryogenesis to apoptosis and pathogen invasions.

Adenoviruses, Human↗

PubMed2003

Acylsulfonamide-containing PTP1B inhibitors designed to mimic an enzyme-bound water of hydration.

Previously, it had been reported that 6-(phosphonodifluoromethyl)-2-naphthoic acid binds to the protein-tyrosine phosphatase PTP1B with its 2-carboxyl group interacting only indirectly through a bridging water molecule. Reported herein is a family of new analogues that utilize acylsulfonamido functionality both to mimic this water of hydration and to provide an additional new site for elaboration not found in the parent carboxyl-containing analogue. Target acylsulfonamides were prepared in two steps from commercially available primary sulfonamides, which were selected based on in silico screening for their potential ability to interact with one of three binding surfaces proximal to the PTP1B catalytic site. In general, modest potency enhancements were observed. Arylacylsulfonamides represent a structure-based extension of inhibitor design that may have broader utility in the development of PTP1B inhibitors.

Amino Acids, Acidic↗

PubMed2003

Discovery of a novel family of CDK inhibitors with the program LIDAEUS: structural basis for ligand-induced disordering of the activation loop.

A family of 4-heteroaryl-2-amino-pyrimidine CDK2 inhibitor lead compounds was discovered with the new database-mining program LIDAEUS through in silico screening. Four compounds with IC(50) values ranging from 17 to 0.9 microM were selected for X-ray crystal analysis. Two distinct binding modes are observed, one of which resembles the hydrogen bonding pattern of bound ATP. In the second binding mode, the ligands trigger a conformational change in the activation T loop by inducing movement of Lys(33) and Asp(145) side chains. The family of molecules discovered provides an excellent starting point for the design and synthesis of tight binding inhibitors, which may lead to a new class of antiproliferative drugs.

Adenosine Triphosphate↗

PubMed1999

Molecular diversity and its analysis.

We have recently developed a novel strategy for the rational design of compounds. This 'in silico screening' approach is based on the design and screening of virtual combinatorial libraries. Screening is performed using defined rules derived from a comprehensive description of active and inactive molecules in a relevant learning set. This strategy allows the development of potential ligands without the necessity of any knowledge of the 3D-structure of the target receptor. Key to the success of such methods is the quality of the information being processed, in particular, the diversity of the data in the context of the molecular population in the libraries concerned. Here, we review the problem of data diversity, its definition and its analysis using a new software tool, named Diverser.

Journal Article↗

PubMedDate not supplied

High-throughput prediction of blood-brain partitioning: a thermodynamic approach.

A high-throughput in silico screening tool for potentially CNS active compounds was developed on the basis of the correlation of solvation free energies and blood-brain partitioning (log(cbrain/cblood) = log BB) data available from experimental sources. Utilizing a thermodynamic approach, solvation free energies were calculated by the fast and efficient generalized Born/surface area continuum solvation model, which enabled us to evaluate more than 10 compounds/min. Our training set involved a structurally diverse set of 55 compounds and yielded a function of log BB = 0.035Gsolv + 0.2592 (r = 0.85, standard error 0.37). Calculation of solvation free energies for 8700 CNS active compounds (CIPSLINE database) revealed that Gsolv is higher than -50 kJ/mol for the 96% of these compounds which can be used as suitable criteria for the identification of compounds preferable for CNS penetration.

Blood-Brain Barrier↗

PubMedDate not supplied

Structure-based classification of antibacterial activity.

The aim of this study was to develop a simple quantitative structure-activity relationship (QSAR) for the classification and prediction of antibacterial activity, so as to enable in silico screening. To this end a database of 661 compounds, classified according to whether they had antibacterial activity, and for which a total of 167 physicochemical and structural descriptors were calculated, was analyzed. To identify descriptors that allowed separation of the two classes (i.e. those compounds with and without antibacterial activity), analysis of variance was utilized and models were developed using linear discriminant and binary logistic regression analyses. Model predictivity was assessed and validated by the random removal of 30% of the compounds to form a test set, for which predictions were made from the model. The results of the analyses indicated that six descriptors, accounting for hydrophobicity and inter- and intramolecular hydrogen bonding, provided excellent separation of the data. Logistic regression analysis was shown to model the data slightly more accurately than discriminant analysis.

Anti-Bacterial Agents↗

PubMedDate not supplied

Similarity metrics for ligands reflecting the similarity of the target proteins.

In this study we evaluate how far the scope of similarity searching can be extended to identify not only ligands binding to the same target as the reference ligand(s) but also ligands of other homologous targets without initially known ligands. This "homology-based similarity searching" requires molecular representations reflecting the ability of a molecule to interact with target proteins. The Similog keys, which are introduced here as a new molecular representation, were designed to fulfill such requirements. They are based only on the molecular constitution and are counts of atom triplets. Each triplet is characterized by the graph distances and the types of its atoms. The atom-typing scheme classifies each atom by its function as H-bond donor or acceptor and by its electronegativity and bulkiness. In this study the Similog keys are investigated in retrospective in silico screening experiments and compared with other conformation independent molecular representations. Studied were molecules of the MDDR database for which the activity data was augmented by standardized target classification information from public protein classification databases. The MDDR molecule set was split randomly into two halves. The first half formed the candidate set. Ligands of four targets (dopamine D2 receptor, opioid delta-receptor, factor Xa serine protease, and progesterone receptor) were taken from the second half to form the respective reference sets. Different similarity calculation methods are used to rank the molecules of the candidate set by their similarity to each of the four reference sets. The accumulated counts of molecules binding to the reference target and groups of targets with decreasing homology to it were examined as a function of the similarity rank for each reference set and similarity method. In summary, similarity searching based on Unity 2D-fingerprints or Similog keys are found to be equally effective in the identification of molecules binding to the same target as the reference set. However, the application of the Similog keys is more effective in comparison with the other investigated methods in the identification of ligands binding to any target belonging to the same family as the reference target. We attribute this superiority to the fact that the Similog keys provide a generalization of the chemical elements and that the keys are counted instead of merely noting their presence or absence in a binary form. The second most effective molecular representation are the occurrence counts of the public ISIS key fragments, which like the Similog method, incorporates key counting as well as a generalization of the chemical elements. The results obtained suggest that ligands for a new target can be identified by the following three-step procedure: 1. Select at least one target with known ligands which is homologous to the new target. 2. Combine the known ligands of the selected target(s) to a reference set. 3. Search candidate ligands for the new targets by their similarity to the reference set using the Similog method. This clearly enlarges the scope of similarity searching from the classical application for a single target to the identification of candidate ligands for whole target families and is expected to be of key utility for further systematic chemogenomics exploration of previously well explored target families.

Algorithms↗

PubMedDate not supplied

Pharmacophore modeling as an efficient tool in the discovery of novel noncompetitive AMPA receptor antagonists.

A three-dimensional pharmacophore model for the binding of noncompetitive AMPA receptor antagonists was developed in order to map common structural features of highly active compounds. This hypothesis, which consists of two hydrophobic regions, one hydrogen bond acceptor and one aromatic region, was successfully used as framework for the design of a new class of allosteric modulators containing a tetrahydroisoquinoline skeleton and for in silico screening. The promising biological results suggested that the identified molecules might be useful "lead compounds" for future drug development.

Animals↗

PubMedDate not supplied

ESP: a method to predict toxicity and pharmacological properties of chemicals using multiple MCASE databases.

We describe here the development of a computer program which uses a new method called Expert System Prediction (ESP), to predict toxic end points and pharmacological properties of chemicals based on multiple modules created by the MCASE artificial intelligence system. The modules are generally based on different biological models measuring related end points. The purpose is to improve the decision making process regarding the overall activity or inactivity of the chemicals and also to enable rapid in silico screening. ESP evaluates the significance of the biophores from a different viewpoint and uses this information for predicting the activity of new chemicals. We have used a unique encoding system to represent relevant features of a chemical in the form of a pattern vector and a genetic artificial neural network (GA-ANN) to gain knowledge of the relationship between these patterns and the overall pharmacological property. The effectiveness of ESP is illustrated in the prediction of general carcinogenicity of a diverse set of chemicals using MCASE male/female rats and mice carcinogenicity modules.

Algorithms↗

PubMed2002

PRO_SELECT: combining structure-based drug design and array-based chemistry for rapid lead discovery. 2. The development of a series of highly potent and selective factor Xa inhibitors.

In silico screening of combinatorial libraries prior to synthesis promises to be a valuable aid to lead discovery. PRO_SELECT, a tool for the virtual screening of libraries for fit to a protein active site, has been used to find novel leads against the serine protease factor Xa. A small seed template was built upon using three iterations of library design, virtual screening, synthesis, and biological testing. Highly potent molecules with selectivity for factor Xa over other serine proteases were rapidly obtained.

Animals↗

PubMed2005

6-Acylamino-2-aminoquinolines as potent melanin-concentrating hormone 1 receptor antagonists. Identification, structure-activity relationship, and investigation of binding mode.

Novel 6-acylamino-2-aminoquinoline melanin-concentrating hormone 1 receptor (MCH1R) antagonists were identified by sequential in silico screening with 3D pharmacophore models derived from a series of benzamide antagonists. The structure-activity relationship exploration by synthesis of analogues found structural demands around the western part of the compounds to be quite specific, whereas much structural freedom was found in the eastern part. While these compounds in general suffered from poor solubility properties, the 4-trifluoromethoxyphenoxyacetamide western appendage provided a favorable combination of activity and solubility properties. The amine in the eastern appendage, originally required by the pharmacophore model and believed to interact with Asp123 in transmembrane 3 of MCH1R, could be removed without diminishing affinity or functional activity of the compounds. Docking studies suggested that the Asp123 interacts preferentially with the nitrogen of the central quinoline. Synthesis and testing of specific analogues supported our revised binding mode hypothesis.

Aminoquinolines↗

PubMed2006

Small-molecule inhibitors of the MDM2-p53 protein-protein interaction based on an isoindolinone scaffold.

From a set of weakly potent lead compounds, using in silico screening and small library synthesis, a series of 2-alkyl-3-aryl-3-alkoxyisoindolinones has been identified as inhibitors of the MDM2-p53 interaction. Two of the most potent compounds, 2-benzyl-3-(4-chlorophenyl)-3-(3-hydroxypropoxy)-2,3-dihydroisoindol-1-one (76; IC(50) = 15.9 +/- 0.8 microM) and 3-(4-chlorophenyl)-3-(4-hydroxy-3,5-dimethoxybenzyloxy)-2-propyl-2,3-dihydroisoindol-1-one (79; IC(50) = 5.3 +/- 0.9 microM), induced p53-dependent gene transcription, in a dose-dependent manner, in the MDM2 amplified, SJSA human sarcoma cell line.

Antineoplastic Agents↗

PubMed2006

Automatic and efficient decomposition of two-dimensional structures of small molecules for fragment-based high-throughput docking.

The computer program DAIM (Decomposition and Identification of Molecules) has been developed to automatically break up compounds in small-molecule libraries for fragment-based docking as well as database analysis. Here, DAIM is evaluated on 130 ligands derived from known crystal structures of ligand-protein complexes. The decomposition and a new fingerprint-based identification technique are used to select anchor fragments for docking. The docking results show that the DAIM selection is superior to size-based or random selection of fragments. To evaluate the usefulness for analyzing the fragment composition of a large library, DAIM is applied to a collection of about 1.85 million commercially available compounds. Interestingly, it is found that the set of most frequent cyclic and acyclic fragments originating from the decomposition of the 1.85 million molecules shows a large overlap with the most frequent fragments in a library of 5120 known drugs. DAIM has been successfully used in the in silico screening for inhibitors of beta-secretase and EphB4 kinase by fragment-based high-throughput docking. Possible future applications for de novo ligand design are briefly discussed.

Amyloid Precursor Protein Secretases↗

PubMedDate not supplied

Rapid quantum mechanical models for the computational estimation of C-H bond dissociation energies as a measure of metabolic stability.

Several relatively inexpensive levels of theory are surveyed together with alternative algorithmic methods for the estimation of C-H bond dissociation energies (BDEs), such energies being useful for the prediction of metabolic stability in drug-like molecules. In particular, bond stretching potentials of several C-H bonds are computed using the AM1, PM3, HF/MIDI!, and B3LYP/MIDI! levels of electronic structure theory, and selected points are fit to Morse and parabolic potentials. BDEs computed by an AM1 fit to the Morse function show the smallest mean unsigned error in prediction (+/- 3-4 kcal/mol) over 32 diverse C-H bonds. An alternative method for correlating the AM1 parabolic force constant from a two-point unrelaxed potential provides only a slightly decreased accuracy and is computationally particularly inexpensive. Both methods should prove to be useful for the rapid in silico screening of drug-like molecules for metabolic stability to C-H bond oxidizing enzymes.

Carbon↗