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At least 307 records · Page 17Linked to original sources
PubMed2003

Discovery of novel low molecular weight inhibitors of IMPDH via virtual needle screening.

Novel, low molecular weight inhibitors of IMPDH have been discovered through the application of a validated virtual screening protocol. A series of 21 IMPDH inhibitors were used to validate the docking procedure. Application of this procedure to the selection of compounds for screening from an in-house database resulted in a 50-fold reduction in the size of the screening set (3425 to 74 compounds) and gave a hit-rate of 10% on biological evaluation.

Binding Sites↗
PubMed2004

HierVLS hierarchical docking protocol for virtual ligand screening of large-molecule databases.

To provide practical means for rapidly scanning the extensive experimental combinatorial chemistry libraries now available for high-throughput screening (HTS), it is essential to establish computational virtual ligand screening (VLS) techniques to rapidly identify out of a large library all active compounds against a particular protein target. Toward this goal we developed HierVLS, a fast hierarchical docking approach that starts with a coarse grain conformational search over a large number of configurations filtered with a fast but crude energy function, followed by a succession of finer grain levels, using successively more accurate but more expensive descriptions of the ligand-protein-solvent interactions to filter successively fewer cases. The final step of this procedure optimizes one configuration of the ligand in the protein site using our most accurate energy expression and description of the solvent, which would be impractical for all conformations and sites sampled in the coarse level. HierVLS is based on the HierDock approach, but rather than allowing an hour or more to determine the best binding site and energy for each ligands (as in HierDock), we have adapted our procedure so that it can lead to reliable results while using only 4 min (866 MHz Pentium III processor) per ligand. To validate the accuracy for HierVLS to predict the experimentally observed binding conformation, we considered 37 cocrystal structures comprising 11 target proteins. We find that HierVLS identifies the correct binding mode for all 37 cocrystals. In addition, the calculated binding energies correlate well with available experimental binding constants. To validate how well HierVLS can identify the correct ligand in an extensive library of decoys, we considered a library of over 10 000 molecules. HierVLS identifies 26 out of the 37 cases in the top 2% ranked by binding affinity among the 10 037 molecules. The failures result from either metal-containing sites on the protein or water-mediated ligand-protein interactions, which we anticipate can be solved within the constraints of practical VLS. We then applied HierVLS to screen a 55000-compound virtual library against the target protein-tyrosine phosphatase 1B (ptp1b). The top 250 compounds by binding affinity included all six ptp1b cocrystal ligands added to the library plus three other experimentally confirmed binders. The best (top 1) binder is an experimentally confirmed positive. We conclude that HierVLS is useful for selecting leads for a particular target out of large combinatorial databases.

Carbonic Anhydrase II↗
PubMedDate not supplied

A novel shape-feature based approach to virtual library screening.

The shape of and the chemical features of a ligand are both critical for biological activity. This paper presents a strategy that uses these descriptors to build a computational model for virtual screening of bioactive compounds. Molecules are represented in a binary shape-feature descriptor space as bit-strings, and their relative activities are used to identify the subset of the bit-string that is most relevant to bioactivity. This subset is used to score virtual libraries. We describe the computational details of the method and present an example validation experiment on thrombin inhibitors.

Computer Simulation↗
PubMed2006

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↗
PubMed2002

Protein-ligand recognition using spherical harmonic molecular surfaces: towards a fast and efficient filter for large virtual throughput screening.

Molecular surfaces are important because surface-shape complementarity is often a necessary condition in protein-ligand interactions and docking studies. We have previously described a fast and efficient method to obtain triangulated surface-meshes by topologically mapping ellipsoids on molecular surfaces. In this paper, we present an extension of our work to spherical harmonic surfaces in order to approximate molecular surfaces of both ligands and receptor-cavities and to easily check the surface-shape complementarity. The method consists of (1) finding lobes and holes on both ligand and cavity surfaces using contour maps of radius functions with spherical harmonic expansions, (2) superposing the surfaces around a given binding site by minimizing the distance between their respective expansion coefficients. This docking procedure capabilities was demonstrated by application to 35 protein-ligand complexes of known crystal structures. The method can also be easily and efficiently used as a filter to detect in a large conformational sampling the possible conformations presenting good complementarity with the receptor site, and being, therefore, good candidates for further more elaborate docking studies. This "virtual screening" was demonstrated on the platelet thrombin receptor.

HIV Protease↗
PubMed2004

Development of small molecules that mimic the binding of omega-conotoxins at the N-type voltage-gated calcium channel.

Cone snails (Conidae) are marine predators with some extraordinary features. Their venom contains a hundred or more peptides that target numerous ion channels and receptors in mammals, including several that are involved in disease. omega-Conotoxins from fish hunting snails are 24-27 residue peptides with a rigid 4-loop cysteine framework that target the N-type voltage-gated calcium channel (VGCC). Two omega-conotoxins, MVIIA and CVID are currently in clinical development for chronic pain management (Ziconotide or Prialt, and AM336, respectively). In an attempt to develop small molecule equivalents of CVID, we defined the Calpha-Cbeta vectors of the residues believed to be important for binding to the N-type VGCC. Using these vectors, we undertook a virtual screening of virtual libraries approach to identify compounds that matched the pharmacophore. Cyclic pentapeptides containing residues of loop 2 of CVID, with one or more being a D-amino acid were designed and synthesised and were found to be active at the N-type VGCC (IC50 approximately 20 microM). Agreeing with the specificity profile of CVID, molecules were inactive at the P/Q-type VGCC.

Animals↗
PubMed2004

Transforming the TGFbeta pathway: convergence of distinct lead generation strategies on a novel kinase pharmacophore for TbetaRI (ALK5).

The pathological activation of the transforming growth factor beta (TGFbeta) pathway plays a critical role in the progression of fibrotic diseases and also enhances tumor invasiveness and metastasis. Due to its central role in TGFbeta signaling, the TGFbeta type I receptor (TbetaRI) is emerging as an exciting target for blockade of the TGFbeta pathway. In this review we will discuss how three independent drug discovery strategies, ie, target-hopping, high-throughput screening and virtual screening, have converged in the identification of inhibitors of TalphaRI kinase. Structural studies have provided insight into the potency and selectivity of these inhibitors and form the basis for structure-based design optimization strategies. These efforts have enabled the production of potent, selective inhibitors for dissecting the TGFalpha pathway and assessing the usefulness of TalphaRI blockade in the treatment of fibrotic diseases and cancer.

Activin Receptors, Type I↗
PubMed2005

Knowledge-driven lead discovery.

Virtual screening encompasses several computational approaches which have proven valuable for identifying novel leads. These approaches rely on available information. Herein, we review recent successful applications of virtual screening. The extension of virtual screening methodologies to target families is also briefly discussed.

Artificial Intelligence↗
PubMed2007

[Docking method for drug discovery].

The effective integration of detailed structural information with computational chemistry, medicinal chemistry, and informatics transforms the dream of virtual screening into reality. One of the most important technologies essential for virtual screening is an effective docking method to find molecules that efficaciously interact with their target molecules. Since an efficient docking method can be a powerful tool for virtual screening, many different approaches to solving docking problems have been proposed. Docking problems have not yet been solved and none of the currently available programs are perfect in predicting all possible scenarios. Despite the limits and imperfections of the methodology, currently available docking methods are very useful for drug discovery. The basic principles and limits of docking methods together with matters for attention in applying the methods are described in this paper.

Binding Sites↗
PubMed2001

Colon cancer screening with virtual colonoscopy: promise, polyps, politics.

Virtual colonoscopy (CT colonography) promises to become a primary method for colorectal cancer screening and return radiologists to a major role in colon cancer prevention. Results from major centers in the United States show accuracy to be comparable to conventional colonoscopy for detection of polyps of significant size--that is, greater than 10 mm--with few false-positives. The advent of virtual colonoscopy has also heightened awareness of the natural history of colonic polyps, particularly in terms of identifying an appropriate target size for detection in colorectal screening programs. Small polyps (<10 mm) are often either hyperplastic on histology or are unlikely to progress to frank cancer in the patient's lifetime and are therefore of little clinical significance for the average adult. Thus, the rationale for detecting and removing each and every colonic polyp regardless of size has come under increasing scrutiny in the context of cost-benefit analysis of various test strategies for colorectal cancer screening. Virtual colonoscopy may allow patients to obtain reliable information about the status of their colonic mucosa noninvasively and thus make a more informed decision as to whether to proceed to conventional colonoscopy for polypectomy.

Colonic Polyps↗
PubMed2004

Crystal structure of avian aminoimidazole-4-carboxamide ribonucleotide transformylase in complex with a novel non-folate inhibitor identified by virtual ligand screening.

Aminoimidazole-4-carboxamide ribonucleotide transformylase (AICAR Tfase), one of the two folate-dependent enzymes in the de novo purine biosynthesis pathway, is a promising target for anti-neoplastic chemotherapy. Although classic antifolates, such as methotrexate, have been developed as anticancer agents, their general toxicity and drug resistance are major issues associated with their clinical use and future development. Identification of inhibitors with novel scaffolds could be an attractive alternative. We present here the crystal structure of avian AICAR Tfase complexed with the first non-folate based inhibitor identified through virtual ligand screening of the National Cancer Institute Diversity Set. The inhibitor 326203-A (2-[5-hydroxy-3-methyl-1-(2-methyl-4-sulfophenyl)-1H-pyrazol-4-ylazo]-4-sulfo-benzoic acid) displayed competitive inhibition against the natural cofactor, 10-formyl-tetrahydrofolate, with a K(i) of 7.1 mum. The crystal structure of AICAR Tfase with 326203-A at 1.8 A resolution revealed a unique binding mode compared with antifolate inhibitors. The inhibitor also accessed an additional binding pocket that is not occupied by antifolates. The sulfonate group of 326203-A appears to form the dominant interaction of the inhibitor with the proposed oxyanion hole through interaction with a helix dipole and Lys(267). An aromatic interaction with Phe(316) also likely contributes to favorable binding. Based on these structural insights, several inhibitors with improved potency were subsequently identified in the National Cancer Institute Compound Library and the Available Chemical Directory by similarity search and molecular modeling methods. These results provide further support for our combined virtual ligand screening rational design approach for the discovery of novel, non-folate-based inhibitors of AICAR Tfase.

Animals↗
PubMedDate not supplied

Impact of conformational flexibility on three-dimensional similarity searching using correlation vectors.

Many three-dimensional (3D) virtual screening concepts, like automated docking or pharmacophore searching, rely on the calculation of a "bioactive" or "receptor-relevant" conformation of a molecule to assess its biological activity. We investigated the dependence of the presence of conformations near the "bioactive" conformation on three-dimensional similarity searching with pharmacophore-based correlation vectors (CATS3D approach). Cocrystal structures of 11 target classes served as queries for virtual screening of a database of annotated ligands. Different numbers of conformations were calculated. Single 3D structures were obtained using the 3D structure generator CORINA and conformational ensembles by the conformation generation program ROTATE. This approach was able to reproduce conformations for high resolution cocrystal structures. For virtual screening we found that using only the CORINA-generated single conformation already resulted in a significant enrichment of isofunctional molecules having the same biological property profile. This observation was also made for ligand classes with many rotatable bonds. Although more similar conformations were considered to be more similar in the CATS3D description, the impact of using multiple conformations on the enrichment of actives was not as high as expected. CATS3D provides an alignment-free three-dimensional virtual screening approach that is less dependent on the presence of conformations which are close to the "bioactive" conformation of a molecule compared to methods that rely on an explicit three-dimensional alignment of molecules.

Algorithms↗
PubMed2005

Fast structure-based virtual ligand screening combining FRED, DOCK, and Surflex.

A protocol was devised in which FRED, DOCK, and Surflex were combined in a multistep virtual ligand screening (VLS) procedure to screen the pocket of four different proteins. One goal was to evaluate the impact of chaining "freely available packages to academic users" on docking/scoring accuracy and CPU time consumption. A bank of 65 660 compounds including 49 known actives was generated. Our procedure is successful because docking/scoring parameters are tuned according to the nature of the binding pocket and because a shape-based filtering tool is applied prior to flexible docking. The obtained enrichment factors are in line with those reported in recent studies. We suggest that consensus docking/scoring could be valuable to some drug discovery projects. The present protocol could process the entire bank for one receptor in less than a week on one processor, suggesting that VLS experiments could be performed even without large computer resources.

Binding Sites↗
PubMed2004

[Human papillomavirus testing in cervical cancer screening].

Virtually all cases of cervical cancer are caused by one of the 18 oncogenic types of human papillomavirus (HPV). It is estimated that 80% of all women will be infected by HPV in a lifetime, and the prevalence of HPV is highest among young, sexually active women and declines with increasing age. The risk of developing high-grade squamous intraepithelial lesions depends on the actual HPV type,the duration of infection, and the viral load. Due to the high prevalence of HPV infection, HPV testing in young women is of little value. The high negative predictive value of this test, combined with nor-mal Papanicolaou smear results, almost ensures that the patient is or will be free of a cancer precursor at the time of testing or in the immediate future. Hence, HPV testing combined with cytology is a reasonable approach in elderly women in order to increase the screening interval to 3-5 years. HPV testing is established for triage of borderline cytology findings of atypical squamous cells of undetermined significance if colposcopy is not performed immediately and if HPV-negative women are rescheduled within 12 months. HPV testing 6 months after cone biopsy allows increasing the follow-up interval due to its high negative predictive value. In atypical glandular lesions not otherwise specified, HPV testing may identify patients requiring immediate treatment. In immunocompromised patients with borderline cytology due to persistent HPV infection, HPV test-ing identifies patients with a low risk of cancer precursors not requiring treatment.

Adult↗
PubMed2005

Gain of human torsional optokinetic nystagmus depends on horizontal disparity.

PURPOSE: To investigate the effects of horizontal disparity on torsional optokinetic nystagmus (tOKN) in humans. METHODS: Ten healthy human subjects were selected for this experiment. Monocular eye movements were recorded three-dimensionally using dual-search coil methods. Torsional OKN was induced by a rotating random-dot pattern (22 degrees in diameter, constant angular velocity: +/-54 deg/s) projected on the virtual screen of the optical see-through, head-mounted display (HMD). The optical distance of the HMD's virtual screen was 2 m. A red LED that could be fixated through the virtual screen of the HMD was located near the center of the rotating random-dot pattern. Horizontal disparity was induced by changing the distance between the fixated target and the subject systematically (1, 1.5, 2, or 3 m; five subjects) or by the prism (+1.5, +0.5, 0, or -0.5 prism-diopter [PD] in each eye; five subjects) in front of the HMD. RESULTS: The average gain with zero horizontal disparity (0.022 +/- 0.008/0.025 +/- 0.014, fixated target at 2 m/fixated target with the plain glass) was significantly higher than the gain with crossed disparity (0.017 +/- 0.003/0.019 +/- 0.008, target at 3 m/with the prism of -0.5 PD) and uncrossed disparity (0.017 +/- 0.002, target at 1 m/with the prism of +1.5 PD; one-way ANOVA, P <0.05). CONCLUSIONS: The horizontal disparity of optokinetic stimulus affects tOKN. Nonzero horizontal disparity decreases the gain of tOKN.

Adult↗
PubMedDate not supplied

How does consensus scoring work for virtual library screening? An idealized computer experiment.

It has been reported recently that consensus scoring, which combines multiple scoring functions in binding affinity estimation, leads to higher hit-rates in virtual library screening studies. This method seems quite independent to the target receptor, the docking program, or even the scoring functions under investigation. Here we present an idealized computer experiment to explore how consensus scoring works. A hypothetical set of 5000 compounds is used to represent a chemical library under screening. The binding affinities of all its member compounds are assigned by mimicking a real situation. Based on the assumption that the error of a scoring function is a random number in a normal distribution, the predicted binding affinities were generated by adding such a random number to the "observed" binding affinities. The relationship between the hit-rates and the number of scoring functions employed in scoring was then investigated. The performance of several typical ranking strategies for a consensus scoring procedure was also explored. Our results demonstrate that consensus scoring outperforms any single scoring for a simple statistical reason: the mean value of repeated samplings tends to be closer to the true value. Our results also suggest that a moderate number of scoring functions, three or four, are sufficient for the purpose of consensus scoring. As for the ranking strategy, both the rank-by-number and the rank-by-rank strategy work more effectively than the rank-by-vote strategy.

Computer Simulation↗
PubMedDate not supplied

VISCANA: visualized cluster analysis of protein-ligand interaction based on the ab initio fragment molecular orbital method for virtual ligand screening.

We have developed a visualized cluster analysis of protein-ligand interaction (VISCANA) that analyzes the pattern of the interaction of the receptor and ligand on the basis of quantum theory for virtual ligand screening. Kitaura et al. (Chem. Phys. Lett. 1999, 312, 319-324.) have proposed an ab initio fragment molecular orbital (FMO) method by which large molecules such as proteins can be easily treated with chemical accuracy. In the FMO method, a total energy of the molecule is evaluated by summation of fragment energies and interfragment interaction energies (IFIEs). In this paper, we have proposed a cluster analysis using the dissimilarity that is defined as the squared Euclidean distance between IFIEs of two ligands. Although the result of an ordered table by clustering is still a massive collection of numbers, we combine a clustering method with a graphical representation of the IFIEs by representing each data point with colors that quantitatively and qualitatively reflect the IFIEs. We applied VISCANA to a docking study of pharmacophores of the human estrogen receptor alpha ligand-binding domain (57 amino acid residues). By using VISCANA, we could classify even structurally different ligands into functionally similar clusters according to the interaction pattern of a ligand and amino acid residues of the receptor protein. In addition, VISCANA could estimate the correct docking conformation by analyzing patterns of the receptor-ligand interactions of some conformations through the docking calculation.

Binding Sites↗
PubMed2004

Selection, application, and validation of a set of molecular descriptors for nuclear receptor ligands.

A methodology for the selection and validation of nuclear receptor ligand chemical descriptors is described. After descriptors for a targeted chemical space were selected, a virtual screening methodology utilizing this space was formulated for the identification of potential NR ligands from our corporate collection. Using simple descriptors and our virtual screening method, we are able to quickly identify potential NR ligands from a large collection of compounds. As validation of the virtual screening procedure, an 8, 000-membered NR targeted set and a 24, 000-membered diverse control set of compounds were selected from our in-house general screening collection and screened in parallel across a number of orphan NR FRET assays. For the two assays that provided at least one hit per set by the established minimum pEC(50) for activity, the results showed a 2-fold increase in the hit-rate of the targeted compound set over the diverse set.

Artificial Intelligence↗