Virtual high-throughput in silico screening

Seifert, Markus H. J.; Wolf, Kristina K.; Vitt, Daniel

doi:10.1016/s1478-5382(03)02359-x

Cited by 77 publications

(79 citation statements)

References 47 publications

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“…1 The QSAR is the name usually applied to methods of this type that correlate the molecular structure with biological properties. The combination of these methods and others as highthroughput screening (HTS), in chemical data mining, can speed up the identification of optimal lead structures, 3 reducing the time in the drug discovery pipeline.…”

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confidence: 99%

Atom- and Bond-Based 2D TOMOCOMD-CARDD Approach and Ligand-Based Virtual Screening for the Drug Discovery of New Tyrosinase Inhibitors

Casañola-Martín¹,

Marrero-Ponce²,

Khan³

et al. 2008

SLAS Discovery

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Two-dimensional atom-and bond-based TOMOCOMD-CARDD descriptors and linear discriminant analysis (LDA) are used in this report to perform a quantitative structure-activity relationship (QSAR) study of tyrosinase-inhibitory activity. A database of inhibitors of the enzyme is collected for this study, within 246 highly dissimilar molecules presenting antityrosinase activity. In total, 7 discriminant functions are obtained by using the whole set of atom-and bond-based 2D indices. All the LDA-based QSAR models show accuracies above 90% in the training set and values of the Matthews correlation coefficient (C) varying from 0.85 to 0.90. The external validation set shows globally good classifications between 89% and 91% and C values ranging from 0.75 to 0.81. Finally, QSAR models are used in the selection/identification of the 20 new dicoumarins subset to search for tyrosinase inhibitory activity. Theoretical and experimental results show good correspondence between one another. It is important to remark that most compounds in this series exhibit a more potent inhibitory activity against the mushroom tyrosinase enzyme than the reference compound, Kojic acid (IC 50 = 16.67 μM), resulting in a novel nucleus base (lead) with antityrosinase activity, and this could serve as a starting point for the drug discovery of novel tyrosinase inhibitor lead compounds. (Journal of Biomolecular Screening 2008:1014-1024 Key words: TOMOCOMD-CARDD descriptor, LDA-based QSAR model, tyrosinase-inhibitor compound, ligand-based virtual screening, dicoumarinChemoinformatics is the combination of chemical synthesis, biological screening and data analysis to guide drug discovery and development.Blake FJ. Integrating cheminformatic analysis in combinatorial chemistry.

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confidence: 99%

Atom- and Bond-Based 2D TOMOCOMD-CARDD Approach and Ligand-Based Virtual Screening for the Drug Discovery of New Tyrosinase Inhibitors

Casañola-Martín¹,

Marrero-Ponce²,

Khan³

et al. 2008

SLAS Discovery

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“…The binding site for IE has been mapped to the BED side of the N-terminal immunoglobulin-like domain (4,15) and shows subtle differences in the contact residues used by ICAM 1-binding P. falciparum antigenic variants (28). The DE loop appears to be a common feature of the ICAM 1 binding sites for the three variants tested and so was selected to screen a library of small-molecule structures in silico using a molecular-alignment technique based on the program package 4Scan (22). Thirty-six compounds were identified as having structures similar to that of the DE loop of human ICAM 1, and they were tested for the ability to inhibit adhesion of IE to ICAM 1 under flow conditions.…”

mentioning

confidence: 99%

Rational Design of Anticytoadherence Inhibitors forPlasmodium falciparumBased on the Crystal Structure of Human Intercellular Adhesion Molecule 1

Dormeyer¹,

Adams

Krämer³

et al. 2006

Antimicrob Agents Chemother

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Adhesion of Plasmodium falciparum-infected erythrocytes (IE) to host endothelium has been associated with pathology in malaria. Although the interaction with endothelial cells can be complex due to the relatively large number of host receptors available for binding, specific proteins have been identified that are more commonly used than others. For example, binding to intercellular adhesion molecule 1 (ICAM 1) is found frequently in parasites from pediatric cases of malaria. The binding site for P. falciparum-infected erythrocytes on ICAM 1 has been mapped in some detail and is distinct from the site for lymphocyte function-associated antigen 1 (LFA-1). Part of the ICAM 1 binding site for P. falciparum-infected erythrocytes (the DE loop) was used to screen a library of compounds based on its structure (derived from the crystal structure of human ICAM 1). This resulted in the identification of 36 structural mimeotopes as potential competitive inhibitors of binding. One of these compounds, (؉)-epigalloyl-catechin-gallate [(؉)-EGCG], was found to inhibit IE adhesion to ICAM 1 in a dose-dependent manner with two variant ICAM 1-binding parasite lines, providing the first example of a potential mimeotope-based anticytoadherence inhibitor for Plasmodium falciparum.Malaria imposes a huge burden of mortality and morbidity in developing countries (25), particularly in sub-Saharan Africa, where it is responsible for over 1 million deaths per year. Most of these are caused by infection with Plasmodium falciparum, one of four human malaria parasites and the only one to undergo significant adhesion to host endothelium, resulting in the sequestration of mature erythrocytic-stage infected erythrocytes (IE) from the peripheral circulation. The pathology of P. falciparum malaria is complex and comprises a number of syndromes, at least some of which are thought to be related to the ability of IE to adhere to host small-vessel endothelium. Several endothelial receptors have been implicated in this interaction (for a review, see reference 9), including intercellular adhesion molecule 1 (ICAM 1) (5). For IE that use ICAM 1, the receptor appears to be an important component of binding, as inhibition using specific monoclonal antibodies reduces cytoadherence to almost background levels despite the presence of other receptors, such as CD36 (12). Although there is some evidence associating sequestration with severe disease, the identification of specific receptor usage linked with pathology has been difficult, with different studies producing conflicting conclusions. In one large study in Kenya, the ability of patient isolates to bind to ICAM 1 was linked to disease (with a trend toward cerebral malaria, a serious, life-threatening manifestation of disease) (14). However, other studies have shown no effect (18). Despite these difficulties, it seems likely that being able to prevent or reverse adhesion to endothelium will be beneficial in acute disease by providing direct access by host clearance systems to the sequestered mass of parasit...

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“…By means of the procedures mentioned above, instead of assaying a large number of chemicals in a series of biological tests, one "virtually assays" these compounds by evaluating their activities with the models developed to this effect; this process is known today as computational (virtual or in silico) screening [142 -144]. Virtual screening techniques may be classified according to their particular modeling of molecular recognition and to the type of algorithm used in database searching [69,142,143]. If the target (or at least its active site) 3-D structure is known, one of the structure-based virtual screening methods can be applied.…”

Section: Cross-validation Methods As the Key For Qsar Model Internal mentioning

confidence: 99%

Discovery of Novel Trichomonacidals Using LDA‐Driven QSAR Models and Bond‐Based Bilinear Indices as Molecular Descriptors

et al. 2009

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Few years ago, the World Health Organization estimated the number of adults with trichomoniasis at 170 million worldwide, more than the combined numbers for gonorrhea, syphilis, and chlamydia. To combat this sexually transmitted disease, Metronidazole (MTZ) has emerged, since 1959, as a powerful drug for the systematic treatment of infected patients. However, increasing resistance to MTZ, adverse effects associated to high-dose MTZ therapies and very expensive conventional technologies related to the development of new trichomonacidals necessitate novel computational methods that shorten the drug discovery pipeline. Therefore, bond-based bilinear indices, new 2-D bond-based TOMOCOMD-CARDD Molecular Descriptors (MDs), and Linear Discriminant Analysis (LDA) are combined to discover novel antitrichomonal agents. Generated models, using non-stochastic and stochastic indices, are able to classify correctly the 90.11% (93.75%) and the 87.92% (87.50%) of chemicals in the training (test) sets, respectively. In addition, they show large Matthews correlation coefficients (C) of 0.80 (0.86) and 0.76 (0.71) for the training (test) sets, respectively. The result of predictions on the 10% full-out cross-validation test also evidences the quality of both models. In order to test the models predictive power, 12 compounds, already proved against Trichomonas vaginalis (Tv), are screened in a simulated virtual screening experiment. As a result, they correctly classified 9 out of 12 (75.00%) and 10 out of 12 (83.33%) of the chemicals, respectively, which were the most important criteria to validate the models. Finally, in order to prove the reach of TOMOCOMD-CARDD approach and to discover new trichomonacidals, these classification functions were applied to a set of QSAR Comb. Sci. 28, 2009, No. 1, 9 -26 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 9 * To whom correspondence should be addressed (contact for chem-and bioinformatics methods) ** Contact for biological assays *** Contact for chemical methods Full Paperseight chemicals which, in turn, were synthesized and tested toward in vitro activity against Tv. As a result, experimental observations confirm theoretical predictions to a great extent, since it is gained a correct classification of 87.50% (7/8) of chemicals. Biological tests also show several candidates as antitrichomonals, since almost all the compounds [VAM2-(3 -8)] exhibit pronounced cytocidal activities of 100% at the concentration of 100 mg/mL and at 24 h (48 h) but VAM2 -2: 99.37% (100%), and it is remarkable that these compounds do not show toxic activity in macrophage assays at this concentration. The Quantitative Structure -Activity Relationship (QSAR) models presented here could significantly reduce the number of synthesized and tested compounds as well as could act as virtual shortcuts to new chemical entities with trichomonacidal activity.

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Virtual high-throughput in silico screening

Cited by 77 publications

References 47 publications

Atom- and Bond-Based 2D TOMOCOMD-CARDD Approach and Ligand-Based Virtual Screening for the Drug Discovery of New Tyrosinase Inhibitors

Atom- and Bond-Based 2D TOMOCOMD-CARDD Approach and Ligand-Based Virtual Screening for the Drug Discovery of New Tyrosinase Inhibitors

Rational Design of Anticytoadherence Inhibitors forPlasmodium falciparumBased on the Crystal Structure of Human Intercellular Adhesion Molecule 1

Discovery of Novel Trichomonacidals Using LDA‐Driven QSAR Models and Bond‐Based Bilinear Indices as Molecular Descriptors

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