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At least 595 records · Page 33Linked to original sources
PubMed2003

Fast 3D molecular superposition and similarity search in databases of flexible molecules.

We present a new method (fFLASH) for the virtual screening of compound databases that is based on explicit three-dimensional molecular superpositions. fFLASH takes the torsional flexibility of the database molecules fully into account, and can deal with an arbitrary number of conformation-dependent molecular features. The method utilizes a fragmentation-reassembly approach which allows for an efficient sampling of the conformational space. A fast clique-based pattern matching algorithm generates alignments of pairs of adjacent molecular fragments on the rigid query molecule that are subsequently reassembled to complete database molecules. Using conventional molecular features (hydrogen bond donors and acceptors, charges, and hydrophobic groups) we show that fFLASH is able to rapidly produce accurate alignments of medium-sized drug-like molecules. Experiments with a test database containing a diverse set of 1780 drug-like molecules (including all conformers) have shown that average query processing times of the order of 0.1 seconds per molecule can be achieved on a PC.

Algorithms↗
PubMedDate not supplied

Superimposition evaluation of ecdysteroid agonist chemotypes through multidimensional QSAR.

The EC50 values for a training set of 66 ecdysteroids and 97 diacylhydrazines were measured in the ecdysteroid-responsive Drosophila melanogaster BII cell line, a prototypical homologous inducible gene expression system. Each of eight superimposition hypotheses for the folded diacylhydrazine conformation was evaluated and ranked on the basis of CoMFA and 4D-QSAR Q2 values for the training set and R2 values for a 52-member test set comprising randomly-chosen diacylhydrazines and chronologically-chosen ecdysteroids for which data became available after model construction. Both 4D-QSAR and CoMFA rate a common superimposition as the preferred one. Two additional superimpositions, with somewhat weaker 4D-QSAR and CoMFA consensus, nonetheless share several important topological features. The resultant QSAR models address the question of relative binding orientation of the two ligand families and can be useful as a virtual screen for new chemotypes.

Animals↗
PubMed2003

Comparison of correlation vector methods for ligand-based similarity searching.

Correlation vector methods were tested for their usefulness in ligand-based virtual screening. Three molecular descriptors--two based on potential pharmacophore points and one on partial atom charges--and three similarity measures--the Manhattan distance, the Euclidian distance and the Tanimoto coefficient--were compared. The alignment-free descriptors seem to be particularly applicable when a course-grain filtering of data sets is required in combination with a high execution speed. Significant enrichment of actives was obtained by retrospective analysis. The cumulative percentages for all three descriptors allow for the retrieval of up to 78% of the active molecules in the first five percent of the reference database. Different descriptors retrieved only weakly overlapping sets of active molecules among the top-ranking compounds. If a single similarity index is to be used, the Manhattan distance seems to be particularly applicable. Generally, none of the three different descriptors tested in this study clearly outperformed the others. The suitability of a descriptor critically depends on the ligand-receptor interaction under investigation. For ligand-based similarity searching it is recommended to exploit several descriptors in parallel.

Algorithms↗
PubMed2004

Identifying the binding mode of a molecular scaffold.

We describe a method for docking of a scaffold-based series and present its advantages over docking of individual ligands, for determining the binding mode of a molecular scaffold in a binding site. The method has been applied to eight different scaffolds of protein kinase inhibitors (PKI). A single analog of each of these eight scaffolds was previously crystallized with different protein kinases. We have used FlexX to dock a set of molecules that share the same scaffold, rather than docking a single molecule. The main mode of binding is determined by the mode of binding of the largest cluster among the docked molecules that share a scaffold. Clustering is based on our 'nearest single neighbor' method [J. Chem. Inf. Comput. Sci., 43 (2003) 208-217]. Additional criteria are applied in those cases in which more than one significant binding mode is found. Using the proposed method, most of the crystallographic binding modes of these scaffolds were reconstructed. Alternative modes, that have not been detected yet by experiments, could also be identified. The method was applied to predict the binding mode of an additional molecular scaffold that was not yet reported and the predicted binding mode has been found to be very similar to experimental results for a closely related scaffold. We suggest that this approach be used as a virtual screening tool for scaffold-based design processes.

Binding Sites↗
PubMed2004

Validation of an empirical RNA-ligand scoring function for fast flexible docking using Ribodock.

We report the design and validation of a fast empirical function for scoring RNA-ligand interactions, and describe its implementation within RiboDock, a virtual screening system for automated flexible docking. Building on well-known protein-ligand scoring function foundations, features were added to describe the interactions of common RNA-binding functional groups that were not handled adequately by conventional terms, to disfavour non-complementary polar contacts, and to control non-specific charged interactions. The results of validation experiments against known structures of RNA-ligand complexes compare favourably with previously reported methods. Binding modes were well predicted in most cases and good discrimination was achieved between native and non-native ligands for each binding site, and between native and non-native binding sites for each ligand. Further evidence of the ability of the method to identify true RNA binders is provided by compound selection ('enrichment factor') experiments based around a series of HIV-1 TAR RNA-binding ligands. Significant enrichment in true binders was achieved amongst high scoring docking hits, even when selection was from a library of structurally related, positively charged molecules. Coupled with a semi-automated cavity detection algorithm for identification of putative ligand binding sites, also described here, the method is suitable for the screening of very large databases of molecules against RNA and RNA-protein interfaces, such as those presented by the bacterial ribosome.

Fluorescence Resonance Energy Transfer↗
PubMed2025

Gain-of-function PPM1D mutations attenuate ischemic stroke.

Identification of genetic aberrations in stroke, the second leading cause of death worldwide, is of paramount importance for understanding the disease pathogenesis and generating new therapies. Whole-genome sequencing from 10,241 ischemic stroke patients identified eight patients carrying gain-of-function mutations on coding variants in the protein phosphatase magnesium-dependent 1 δ (PPM1D) gene. Patients carrying PPM1D mutations exhibit better stroke-related clinical phenotypes, including improvements in peripheral inflammation, fibrinogen, low-density lipoprotein, cholesterol and plateletcrit level. Experimental brain ischemia in Ppm1d-deficient (Ppm1d-/-) mice resulted in enlarged lesions and pronounced neurological impairments. Spatial transcriptomics revealed a distinct Ppm1d-associated gene expression pattern, indicating disrupted endothelial homeostasis during ischemic brain injury. Proteomic analysis demonstrated that differentially expressed proteins in primary brain endothelial cells from Ppm1d-/- mice were significantly enriched in the peroxisome proliferator-activated receptors (PPARs)-mediated metabolic signaling. Mechanistically, Ppm1d deficiency promoted aberrant fatty acid β-oxidation and increased oxidative stress, which impaired endothelial cell function through the PPARα pathway. A small molecule, T2755, was identified to engage Trp427 and stabilize PPM1D, thereby mitigating ischemic brain injury in mice. Collectively, we find that PPM1D protects against ischemic brain injury and validates its pharmacological stabilizer T2755 as a promising therapy for ischemic stroke. Gain-of-function PPM1D mutations attenuate ischemic cerebral injury. Whole-genome sequencing data of 10,241 ischemic stroke patients from the Third Chinese National Stroke Registry (CNSR-III) identified eight patients with gain-of-function mutations in the protein phosphatase magnesium-dependent 1 δ (PPM1D) gene (17q23.2). These mutation carriers displayed improved peripheral inflammation, decreased fibrinogen, low-density lipoprotein, cholesterol and plateletcrit level. Ppm1d-deficient (Ppm1d-/-) mice exhibited exacerbated stroke outcomes, characterized by enlarged infarct volumes, disrupted cerebrovascular architecture, and enhanced neuro-inflammation. Mechanistically, Ppm1d deficiency induced the disturbance of endothelial fatty acid metabolism involving the PPARα pathway. Through integrated computational modeling, virtual screening, and in vitro validation, T2755 was identified as a small molecule PPM1D stabilizer. Pharmacological PPM1D stabilization with T2755 significantly attenuated ischemic brain injury in murine models.

Aged↗
PubMed2005

The Akt/PKB pathway: molecular target for cancer drug discovery.

The serine/threonine kinase Akt/PKB pathway presents an exciting new target for molecular therapeutics, as it functions as a cardinal nodal point for transducing extracellular (growth factor and insulin) and intracellular (receptor tyrosine kinases, Ras and Src) oncogenic signals. In addition, alterations of the Akt pathway have been detected in a number of human malignancies. Ectopic expression of Akt, especially constitutively activated Akt, is sufficient to induce oncogenic transformation of cells and tumor formation in transgenic mice as well as chemoresistance. Akt has a wide range of downstream targets that regulate tumor-associated cell processes such as cell growth, cell cycle progression, survival, migration, epithelial-mesenchymal transition and angiogenesis. Blockage of Akt signaling results in apoptosis and growth inhibition of tumor cells with elevated Akt. The observed dependence of certain tumors on Akt signaling for survival and growth has wide implications for cancer therapy, offering the potential for preferential tumor cell killing. In the last several years, through combinatorial chemistry, high-throughput and virtual screening, and traditional medicinal chemistry, a number of inhibitors of the Akt pathway have been identified. This review focuses on ongoing translational efforts to therapeutically target the Akt pathway.

Antineoplastic Agents↗
PubMed2001

Site-specific molecular design and its relevance to pharmacogenomics and chemical biology.

The emergence of the new discipline of pharmacogenomics reflects the growing convergence of chemical and genomic space. The massive information-driven growth in both computational chemistry and structural biology is leading to unprecedented opportunities in both chemical and biological design. In this paper we relate current opinion in structural biology to recent developments in computational drug design. Sequence information now permits protein structure prediction and, together with experimental protein structure determination, a complete database of ligand-binding sites and protein-protein interactions can be assembled. When aligned with site exploration and virtual screening, this information provides a foundation for structure-based pharmacogenomics. In association with chemical genomics, structure-based design will allow major new insights into a compound's biological and pharmaceutical properties.

Binding Sites↗
PubMed2004

Molecular similarity: a key technique in molecular informatics.

Molecular Informatics utilises many ideas and concepts to find relationships between molecules. The concept of similarity, where molecules may be grouped according to their biological effects or physicochemical properties has found extensive use in drug discovery. Some areas of particular interest have been in lead discovery and compound optimisation. For example, in designing libraries of compounds for lead generation, one approach is to design sets of compounds "similar" to known active compounds in the hope that alternative molecular structures are found that maintain the properties required while enhancing e.g. patentability, medicinal chemistry opportunities or even in achieving optimised pharmacokinetic profiles. Thus the practical importance of the concept of molecular similarity has grown dramatically in recent years. The predominant users are pharmaceutical companies, employing similarity methods in a wide range of applications e.g. virtual screening, estimation of absorption, distribution, metabolism, excretion and toxicity (ADME/Tox) and prediction of physicochemical properties (solubility, partitioning etc.). In this perspective, we discuss the representation of molecular structure (descriptors), methods of comparing structures and how these relate to measured properties. This leads to the concept of molecular similarity, its various definitions and uses and how these have evolved in recent years. Here, we wish to evaluate and in some cases challenge accepted views and uses of molecular similarity. Molecular similarity, as a paradigm, contains many implicit and explicit assumptions in particular with respect to the prediction of the binding and efficacy of molecules at biological receptors. The fundamental observation is that molecular similarity has a context which both defines and limits its use. The key issues of solvation effects, heterogeneity of binding sites and the fundamental problem of the form of similarity measure to use are addressed.

Algorithms↗
PubMed2006

Molecular mechanics methods for predicting protein-ligand binding.

Ligand binding affinity prediction is one of the most important applications of computational chemistry. However, accurately ranking compounds with respect to their estimated binding affinities to a biomolecular target remains highly challenging. We provide an overview of recent work using molecular mechanics energy functions to address this challenge. We briefly review methods that use molecular dynamics and Monte Carlo simulations to predict absolute and relative ligand binding free energies, as well as our own work in which we have developed a physics-based scoring method that can be applied to hundreds of thousands of compounds by invoking a number of simplifying approximations. In our previous studies, we have demonstrated that our scoring method is a promising approach for improving the discrimination between ligands that are known to bind and those that are presumed not to, in virtual screening of large compound databases. In new results presented here, we explore several improvements to our computational method including modifying the dielectric constant used for the protein and ligand interiors, and empirically scaling energy terms to compensate for deficiencies in the energy model. Future directions for further improving our physics-based scoring method are also discussed.

Algorithms↗
PubMed2005

Discovering COX-inhibiting constituents of Morus root bark: activity-guided versus computer-aided methods.

The aim of this study was to compare the efficiency of two well known approaches for the discovery of the bioactive principle/s in medicinal plants, namely the activity-guided isolation versus the computer-aided drug discovery by means of virtual screening (VS) techniques. Morus root bark of Morus sp. L. (Moraceae) was selected as application example for the discovery of compounds with anti-inflammatory activity. The two cyclooxygenase isoenzymes COX-1 and COX-2 were chosen as targets and the corresponding pharmacophore models were generated by our research. The activity-guided fractionation of the methanol extract of the root bark resulted in the isolation of nine compounds. Their structures were elucidated by mass spectrometry, 1- and 2-dimensional NMR experiments and identified as moracins B, M, the regioisomers O/P as a mixture, and sanggenons B, C, D, E and O. The COX-1 and COX-2 inhibiting activities of these compounds were established in an enzyme assay and compared with the predicted hits obtained from the VS. Sanggenons C, E, and O, that were tested the first time for an inhibitory effect on COX-1 and -2, showed IC50 values of 10-14 microM, and 40-50 microM, respectively. The results show that the COX activities obtained for the sanggenons are correctly predicted by the in silico filtering experiment. In the case of the isolated moracins, however, it failed because the COX inhibiting activities of moracins M and P/O were not retrieved by the VS. Structure-activity relationships of the isolated compounds are discussed as well as potential pitfalls and advantages of the applied strategies.

Cyclooxygenase 1↗
PubMed2006

Integrated in silico tools for exploiting the natural products' bioactivity.

Whereas computational methods for molecular design are well established in medicinal chemistry research, their application in the field of natural products is still not exhaustively explored. This article gives a short introduction into both the potential for the application of computer-assisted approaches, such as pharmacophore modelling, virtual screening, docking, and neural networking to efficiently access the bioactive metabolites, and the requirements and limitations related to this specific field. The challenge is which selection criteria and/or multiple filtering tools to apply for a target-oriented isolation of potentially bioactive secondary metabolites. Application examples are provided where in silico tools and classical methods used by natural product scientists are used in an effort to maximize their efficacy in drug discovery. Thus, integrated computer-assisted strategies may help to process the huge amount of available structural and biological information in a reasonably short time for a straightforward search of bioactive natural products.

Computer-Aided Design↗
PubMed2004

Rational design and characterization of a Rac GTPase-specific small molecule inhibitor.

The signaling pathways mediated by Rho family GTPases have been implicated in many aspects of cell biology. The specificity of the pathways is achieved in part by the selective interaction between Dbl family guanine nucleotide exchange factors (GEFs) and their Rho GTPase substrates. Here, we report a first-generation small-molecule inhibitor of Rac GTPase targeting Rac activation by GEF. The chemical compound NSC23766 was identified by a structure-based virtual screening of compounds that fit into a surface groove of Rac1 known to be critical for GEF specification. In vitro it could effectively inhibit Rac1 binding and activation by the Rac-specific GEF Trio or Tiam1 in a dose-dependent manner without interfering with the closely related Cdc42 or RhoA binding or activation by their respective GEFs or with Rac1 interaction with BcrGAP or effector PAK1. In cells, it potently blocked serum or platelet-derived growth factor-induced Rac1 activation and lamellipodia formation without affecting the activity of endogenous Cdc42 or RhoA. Moreover, this compound reduced Trio or Tiam1 but not Vav, Lbc, Intersectin, or a constitutively active Rac1 mutant-stimulated cell growth and suppressed Trio, Tiam1, or Ras-induced cell transformation. When applied to human prostate cancer PC-3 cells, it was able to inhibit the proliferation, anchorage-independent growth and invasion phenotypes that require the endogenous Rac1 activity. Thus, NSC23766 constitutes a Rac-specific small-molecule inhibitor that could be useful to study the role of Rac in various cellular functions and to reverse tumor cell phenotypes associated with Rac deregulation.

Aminoquinolines↗
PubMed2000

Rational discovery of novel nuclear hormone receptor antagonists.

Nuclear hormone receptors (NRs) are potential targets for therapeutic approaches to many clinical conditions, including cancer, diabetes, and neurological diseases. The crystal structure of the ligand binding domain of agonist-bound NRs enables the design of compounds with agonist activity. However, with the exception of the human estrogen receptor-alpha, the lack of antagonist-bound "inactive" receptor structures hinders the rational design of receptor antagonists. In this study, we present a strategy for designing such antagonists. We constructed a model of the inactive conformation of human retinoic acid receptor-alpha by using information derived from antagonist-bound estrogen receptor-alpha and applied a computer-based virtual screening algorithm to identify retinoic acid receptor antagonists. Thus, the currently available crystal structures of NRs may be used for the rational design of antagonists, which could lead to the development of novel drugs for a variety of diseases.

Algorithms↗
PubMed1999

Mammalian mitochondrial ribosomal proteins (2). Amino acid sequencing, characterization, and identification of corresponding gene sequences.

Four different classes of mammalian mitochondrial ribosomal proteins were identified and characterized. Mature proteins were purified from bovine liver and subjected to N-terminal or matrix-assisted laser-desorption mass spectroscopic amino acid sequencing after tryptic in-gel digestion and high pressure liquid chromatography separation of the resulting peptides. Peptide sequences obtained were used to virtually screen expressed sequence tag data bases from human, mouse, and rat. Consensus cDNAs were assembled in silico from various expressed sequence tag sequences identified. Deduced mammalian protein sequences were characterized and compared with ribosomal protein sequences of Escherichia coli and yeast mitochondria. Significant sequence similarities to ribosomal proteins of other sources were detected for three out of four different mammalian protein classes determined. However, the sequence conservation between mitochondrial ribosomal proteins of mammalian and yeast origin is much less than the sequence conservation between cytoplasmic ribosomal proteins of the same species. In particular, this is shown for the mammalian counterparts of the E. coli EcoL2 ribosomal protein (MRP-L14), that do not conserve the specific and functional highly important His(229) residue of E. coli and the corresponding yeast mitochondrial Rml2p.

Amino Acid Sequence↗
PubMed2001

Type-specific regulation of adenylyl cyclase. Selective pharmacological stimulation and inhibition of adenylyl cyclase isoforms.

Crystallographic studies have elucidated the binding mechanism of forskolin and P-site inhibitors to adenylyl cyclase. Accordingly, computer-assisted drug design has enabled us to identify isoform-selective regulators of adenylyl cyclase. After examining more than 200 newly synthesized derivatives of forskolin, we found that the modification at the positions of C6 and C7, in general, enhances isoform selectivity. The 6-(3-dimethylaminopropionyl) modification led to an enhanced selectivity for type V, whereas 6-[N-(2-isothiocyanatoethyl) aminocarbonyl] and 6-(4-acrylbutyryl) modification led to an enhanced selectivity for type II. In contrast, 2'-deoxyadenosine 3'-monophosphate, a classical and 3'-phosphate-substituted P-site inhibitor, demonstrated a 27-fold selectivity for inhibiting type V relative to type II, whereas 9-(tetrahydro-2-furyl) adenine, a ribose-substituted P-site ligand, showed a markedly increased, 130-fold selectivity for inhibiting type V. Consequently, on the basis of the pharmacophore analysis of 9-(tetrahydro-2-furyl) adenine and adenylyl cyclase, a novel non-nucleoside inhibitor, 2-amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone (NKY80), was identified after virtual screening of more than 850,000 compounds. NKY80 demonstrated a 210-fold selectivity for inhibiting type V relative to type II. More importantly, the combination of a type III-selective forskolin derivative and 9-(tetrahydro-2-furyl) adenine or NKY80 demonstrated a further enhanced selectivity for type III stimulation over other isoforms. Our data suggest the feasibility of adenylyl cyclase isoform-targeted regulation of cyclic AMP signaling by pharmacological reagents, either alone or in combination.

Adenylyl Cyclase Inhibitors↗
PubMed2003

Protonation states of methionine aminopeptidase and their relevance for inhibitor binding and catalytic activity.

We have performed a computational study of different protomeric states of the methionine aminopeptidase active site using a combined quantum-mechanical/molecular mechanical simulation approach. The aim of this study was to clarify the native protonation state of the enzyme, which is needed for the development of novel irreversible inhibitors that can possibly be used as antiangiogenic and antibiotic drugs by virtual screening and other drug design methods. The results of the simulations indicated that two protonation states are possible without disturbing the overall geometry of the active site. We then verified experimentally the presence of the two protonation states by studying the substrate hydrolysis and inhibitor binding reactions at different pH values and come to the conclusion that one of the protomeric states is relevant for inhibitor binding, whereas the other is relevant for substrate hydrolysis. This result has implications for the development of other inhibitors of this class of enzymes and adds a new perspective to the pharmacological properties of the antiangiogenic drug fumagillin, which is an irreversible inhibitor of the human methionine aminopeptidase type II.

Aminopeptidases↗
PubMed2006

Quaternary ammonium compounds as water channel blockers. Specificity, potency, and site of action.

Excessive water uptake through Aquaporins (AQP) can be life-threatening and reversible AQP inhibitors are needed. Here, we determined the specificity, potency, and binding site of tetraethylammonium (TEA) to block Aquaporin water permeability. Using oocytes, externally applied TEA blocked AQP1/AQP2/AQP4 with IC50 values of 1.4, 6.2, and 9.8 microM, respectively. Related tetraammonium compounds yielded some (propyl) or no (methyl, butyl, or pentyl) inhibition. TEA inhibition was lost upon a Tyr to Phe amino acid switch in the external water pore of AQP1/AQP2/AQP4, whereas the water permeability of AQP3 and AQP5, which lack a corresponding Tyr, was not blocked by TEA. Consistent with experimental data, multi-nanosecond molecular dynamics simulations showed one stable binding site for TEA, but not tetramethyl (TMA), in AQP1, resulting in a nearly 50% water permeability inhibition, which was reduced in AQP1-Y186F due to effects on the TEA inhibitory binding region. Moreover, in the simulation TEA interacted with charged residues in the C (Asp128) and E (Asp185) loop, and the A(Tyr37-Asn42-Thr44) loop of the neighboring monomer, but not directly with Tyr186. The loss of TEA inhibition in oocytes expressing properly folded AQP1-N42A or -T44A is in line with the computationally predicted binding mode. Our data reveal that the molecular interaction of TEA with AQP1 differs and is about 1000-fold more effective on AQPs than on potassium channels. Moreover, the observed experimental and simulated similarities open the way for rational design and virtual screening for AQP-specific inhibitors, with quaternary ammonium compounds in general, and TEA in particular as a lead compound.

Amino Acid Sequence↗