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Virtual Screening (virtual + screening)
Selected Abstracts,tieredScreen' , Layered Virtual Screening Tool for the Identification of Novel Estrogen Receptor Alpha ModulatorsMOLECULAR INFORMATICS, Issue 5 2010Yidong Yang Abstract A novel tiered Structure-Based (SB) Virtual Screening (VS) workflow called tieredScreen was designed and implemented. The automated protocol utilises diverse computational tools in a synergistic manner to reduce false positives and increase the likelihood of converging on putative active molecules. The performance of the novel VS workflow was validated using the Directory of Useful Decoys (DUD) Estrogen Receptor , (ER,) antagonist dataset, and successfully deployed for the identification of novel antagonists of ER, from a screening collection of ca. 160,000 commercially available compounds. As well as yielding nanomolar (nM) active ligands identified previously through a docking only protocol, from a selection of eight virtual hits suggested by tieredScreen, four novel nM ER, binding chemotypes were identified and biologically validated , demonstrating the applicability of a tiered intervention for virtual screening. [source] Generation of Selective TACE Inhibitors: Ligand and Structure Based Molecular Modeling, Virtual Screening, Counter Pharmacophore Screening to Get Selective MoleculesMOLECULAR INFORMATICS, Issue 11-12 2009Malkeet, Singh Bahia Abstract This study describes the ligand based as well as structure based molecular modeling and virtual screening of selective tumor necrosis factor-, converting enzyme (TACE) inhibitors. In ligand based molecular modeling, two statistically reliable pharmacophore models HypoA1 and HypoB1 were generated using a same training set of 22,molecules. HypoA1,consists of two hydrogen bond acceptor and three hydrophobic groups whereas HypoB1 consists of one hydrogen bond donor, one ring aromatic and three hydrophobic groups. Virtual screening was performed with both models in in-house database of 1.2,million molecules. To remove non selective hits from screened molecules, a counter pharmacophore was generated using inhibitors of MMP-1, an important enzyme involved in musculoskeletal degradation. In structure based molecular modeling, docking analysis was performed to explore the important interactions between ligands and protein. On comparison, HypoA1 and HypoB1 were found to be complementing with results of docking analysis suggesting high reliability of both models for their use in virtual screening/designing of new molecules. [source] Abstracts of QSAR-related Publications: Data Base, Virtual ScreeningMOLECULAR INFORMATICS, Issue 4 2009Article first published online: 3 APR 200 First page of article [source] Abstracts of QSAR-related Publications: Data Base, Virtual ScreeningMOLECULAR INFORMATICS, Issue 2 2009Article first published online: 10 FEB 200 First page of article [source] Abstracts of QSAR-related Publications: Data Base, Virtual ScreeningMOLECULAR INFORMATICS, Issue 9 2008Article first published online: 17 SEP 200 First page of article [source] Abstracts of QSAR-related Publications: Data Base, Virtual ScreeningMOLECULAR INFORMATICS, Issue 6 2007Article first published online: 5 JUN 200 No abstract is available for this article. [source] Abstracts of QSAR-related Publications: Data Base Search & Virtual ScreeningMOLECULAR INFORMATICS, Issue 11 2006Article first published online: 8 NOV 200 First page of article [source] Abstracts of QSAR-related Publications: Data Base Search & Virtual ScreeningMOLECULAR INFORMATICS, Issue 10 2006Article first published online: 9 OCT 200 First page of article [source] Abstracts of QSAR-related Publications: Data Base Search & Virtual ScreeningMOLECULAR INFORMATICS, Issue 7 2006Article first published online: 11 JUL 200 No abstract is available for this article. [source] A Fragment-weighted Key-based Similarity Measure for Use in Structural Clustering and Virtual ScreeningMOLECULAR INFORMATICS, Issue 3 2006Marie Munk Jørgensen Abstract A new similarity measure and structural clustering method has been developed in which each structure is fragmented into ring systems, linkers, and side chains, and where the similarity between structures forms a weighted sum of the similarities between each set of fragments. We have applied the MACCS keys as molecular descriptors and identified a number of ways in which to improve the use of these keys for structural clustering and virtual screening. The method has been optimized to reproduce scaffold-biased clustering commonly used in medicinal chemistry. [source] New Allosteric Modulators of Metabotropic Glutamate Receptor 5 (mGluR5) Found by Ligand-Based Virtual ScreeningCHEMBIOCHEM, Issue 4 2005Steffen Renner Ligand-based pharmacophore searching identified new allosteric modulators of metabotropic glutamate receptor 5 (mGluR5), a class III G protein-coupled receptor. This virtual-screening approach can be seen as a working alternative to more demanding structure-based design techniques with the main aim of developing novel lead series. [source] Influenza Virus Neuraminidase Inhibitors: Generation and Comparison of Structure-Based and Common Feature Pharmacophore Hypotheses and Their Application in Virtual Screening.CHEMINFORM, Issue 51 2004Theodora Steindl No abstract is available for this article. [source] Similarity-Based Virtual Screening with a Bayesian Inference NetworkCHEMMEDCHEM, Issue 2 2009Ammar Abdo Abstract An inference network model for molecular similarity searching: The similarity search problem is modeled using inference or evidential reasoning under uncertainty. The inference network model treats similarity searching as an evidential reasoning process in which multiple sources of evidence about compounds and reference structures are combined to estimate resemblance probabilities. Many methods have been developed to capture the biological similarity between two compounds for use in drug discovery. A variety of similarity metrics have been introduced, the Tanimoto coefficient being the most prominent. Many of the approaches assume that molecular features or descriptors that do not relate to the biological activity carry the same weight as the important aspects in terms of biological similarity. Herein, a novel similarity searching approach using a Bayesian inference network is discussed. Similarity searching is regarded as an inference or evidential reasoning process in which the probability that a given compound has biological similarity with the query is estimated and used as evidence. Our experiments demonstrate that the similarity approach based on Bayesian inference networks is likely to outperform the Tanimoto similarity search and offer a promising alternative to existing similarity search approaches. [source] Virtual Screening and Biological Characterization of Novel Histone Arginine Methyltransferase PRMT1 InhibitorsCHEMMEDCHEM, Issue 1 2009Ralf Heinke Abstract Lysine and arginine methyltransferases participate in the posttranslational modification of histones and regulate key cellular functions. Protein arginine methyltransferase,1 (PRMT1) has been identified as an essential component of mixed lineage leukemia (MLL) oncogenic complexes, revealing its potential as a novel therapeutic target in human cancer. The first potent arginine methyltransferase inhibitors were recently discovered by random- and target-based screening approaches. Herein we report virtual and biological screening for novel inhibitors of PRMT1. Structure-based virtual screening (VS) of the Chembridge database composed of 328,000 molecules was performed with a combination of ligand- and target-based in,silico approaches. Nine inhibitors were identified from the top-scored docking solutions; these were experimentally tested using human PRMT1 and an antibody-based assay with a time-resolved fluorescence readout. Among several aromatic amines, an aliphatic amine and an amide were also found to be active in the micromolar range. [source] Thiobarbiturates as Sirtuin Inhibitors: Virtual Screening, Free-Energy Calculations, and Biological TestingCHEMMEDCHEM, Issue 12 2008Urszula Uciechowska Abstract NAD+ -dependent histone deacetylases (sirtuins) are enzymes that cleave acetyl groups from lysine residues in histones and other proteins. Potent selective sirtuin inhibitors are interesting tools for the investigation of the biological functions of these enzymes and may be future drugs for the treatment of cancer or neurodegenerative diseases. Herein we present the results from a protein-based virtual screen of a commercial database with subsequent biological testing of the most promising compounds. The combination of docking and in,vitro experimental testing resulted in the identification of novel sirtuin inhibitors with thiobarbiturate structure. To rationalize the experimental results, free-energy calculations were carried out by molecular mechanics Poisson,Boltzmann/surface area (MM-PBSA) calculations. A significant correlation between calculated binding free energies and measured Sirt2 inhibitory activities was observed. The analyses suggested a molecular basis for the interaction of the identified thiobarbiturate derivatives with human Sirt2. Based on the docking and MM-PBSA calculations we synthesized and tested five further thiobarbiturates. The MM-PBSA method correctly predicted the activity of the novel thiobarbiturates. The identified compounds will be used to further explore the therapeutic potential of sirtuin inhibitors. [source] Generation of Selective TACE Inhibitors: Ligand and Structure Based Molecular Modeling, Virtual Screening, Counter Pharmacophore Screening to Get Selective MoleculesMOLECULAR INFORMATICS, Issue 11-12 2009Malkeet, Singh Bahia Abstract This study describes the ligand based as well as structure based molecular modeling and virtual screening of selective tumor necrosis factor-, converting enzyme (TACE) inhibitors. In ligand based molecular modeling, two statistically reliable pharmacophore models HypoA1 and HypoB1 were generated using a same training set of 22,molecules. HypoA1,consists of two hydrogen bond acceptor and three hydrophobic groups whereas HypoB1 consists of one hydrogen bond donor, one ring aromatic and three hydrophobic groups. Virtual screening was performed with both models in in-house database of 1.2,million molecules. To remove non selective hits from screened molecules, a counter pharmacophore was generated using inhibitors of MMP-1, an important enzyme involved in musculoskeletal degradation. In structure based molecular modeling, docking analysis was performed to explore the important interactions between ligands and protein. On comparison, HypoA1 and HypoB1 were found to be complementing with results of docking analysis suggesting high reliability of both models for their use in virtual screening/designing of new molecules. [source] A poke in the eye: Inhibiting HIV-1 protease through its flap-recognition pocketBIOPOLYMERS, Issue 8 2008Kelly L. Damm Abstract A novel mechanism of inhibiting HIV-1 protease (HIVp) is presented. Using computational solvent mapping to identify complementary interactions and the Multiple Protein Structure method to incorporate protein flexibility, we generated a receptor-based pharmacophore model of the flexible flap region of the semiopen, apo state of HIVp. Complementary interactions were consistently observed at the base of the flap, only within a cleft with a specific structural role. In the closed, bound state of HIVp, each flap tip docks against the opposite monomer, occupying this cleft. This flap-recognition site is filled by the protein and cannot be identified using traditional approaches based on bound, closed structures. Virtual screening and dynamics simulations show how small molecules can be identified to complement this cleft. Subsequent experimental testing confirms inhibitory activity of this new class of inhibitor. This may be the first new inhibitor class for HIVp since dimerization inhibitors were introduced 17 years ago. © 2008 Wiley Periodicals, Inc. Biopolymers 89: 643,652, 2008. 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] Identification and Validation of a Potent Type,II Inhibitor of Inactive Polo-like Kinase,1CHEMMEDCHEM, Issue 11 2009Sarah Keppner Virtual screening using a homology model of human polo-like kinase,1 (Plk1) in an inactive conformation led to the identification of a selective Plk1 inhibitor that decreases proliferation and induces apoptosis. This suggests that type,II Plk1 inhibitors may be considered for the development of cancer therapeutics. [source] In silico prediction and screening of ,-secretase inhibitors by molecular descriptors and machine learning methodsJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 6 2010Xue-Gang Yang Abstract ,-Secretase inhibitors have been explored for the prevention and treatment of Alzheimer's disease (AD). Methods for prediction and screening of ,-secretase inhibitors are highly desired for facilitating the design of novel therapeutic agents against AD, especially when incomplete knowledge about the mechanism and three-dimensional structure of ,-secretase. We explored two machine learning methods, support vector machine (SVM) and random forest (RF), to develop models for predicting ,-secretase inhibitors of diverse structures. Quantitative analysis of the receiver operating characteristic (ROC) curve was performed to further examine and optimize the models. Especially, the Youden index (YI) was initially introduced into the ROC curve of RF so as to obtain an optimal threshold of probability for prediction. The developed models were validated by an external testing set with the prediction accuracies of SVM and RF 96.48 and 98.83% for ,-secretase inhibitors and 98.18 and 99.27% for noninhibitors, respectively. The different feature selection methods were used to extract the physicochemical features most relevant to ,-secretase inhibition. To the best of our knowledge, the RF model developed in this work is the first model with a broad applicability domain, based on which the virtual screening of ,-secretase inhibitors against the ZINC database was performed, resulting in 368 potential hit candidates. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010 [source] SARS-CoV protease inhibitors design using virtual screening method from natural products librariesJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 5 2005Bing Liu Abstract Two natural products databases, the marine natural products database (MNPD) and the traditional Chinese medicines database (TCMD), were used to find novel structures of potent SARS-CoV protease inhibitors through virtual screening. Before the procedure, the databases were filtered by Lipinski's ROF and Xu's extension rules. The results were analyzed by statistic methods to eliminate the bias in target-based database screening toward higher molecular weight compounds for enhancing the hit rate. Eighteen lead compounds were recommended by the screening procedure. They were useful for experimental scientists in prioritizing drug candidates and studying the interaction mechanism. The binding mechanism was also analyzed between the best screening compound and the SARS protein. © 2005 Wiley Periodicals, Inc. J Comput Chem 26: 484,490, 2005 [source] Evaluation of library ranking efficacy in virtual screening,JOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 1 2005Maria Kontoyianni Abstract We present the results of a comprehensive study in which we explored how the docking procedure affects the performance of a virtual screening approach. We used four docking engines and applied 10 scoring functions to the top-ranked docking solutions of seeded databases against six target proteins. The scores of the experimental poses were placed within the total set to assess whether the scoring function required an accurate pose to provide the appropriate rank for the seeded compounds. This method allows a direct comparison of library ranking efficacy. Our results indicate that the LigandFit/Ligscore1 and LigandFit/GOLD docking/scoring combinations, and to a lesser degree FlexX/FlexX, Glide/Ligscore1, DOCK/PMF (Tripos implementation), LigandFit1/Ligscore2 and LigandFit/PMF (Tripos implementation) were able to retrieve the highest number of actives at a 10% fraction of the database when all targets were looked upon collectively. We also show that the scoring functions rank the observed binding modes higher than the inaccurate poses provided that the experimental poses are available. This finding stresses the discriminatory ability of the scoring algorithms, when better poses are available, and suggests that the number of false positives can be lowered with conformers closer to bioactive ones. © 2004 Wiley Periodicals, Inc. J Comput Chem 26: 11,22, 2005 [source] Conformational analysis by intersection: CONANJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 1 2003Andrew Smellie Abstract As high throughput techniques in chemical synthesis and screening improve, more demands are placed on computer assisted design and virtual screening. Many of these computational methods require one or more three-dimensional conformations for molecules, creating a demand for a conformational analysis tool that can rapidly and robustly cover the low-energy conformational spaces of small molecules. A new algorithm of intersection is presented here, which quickly generates (on average <0.5 seconds/stereoisomer) a complete description of the low energy conformational space of a small molecule. The molecule is first decomposed into nonoverlapping nodes N (usually rings) and overlapping paths P with conformations (N and P) generated in an offline process. In a second step the node and path data are combined to form distinct conformers of the molecule. Finally, heuristics are applied after intersection to generate a small representative collection of conformations that span the conformational space. In a study of ,97,000 randomly selected molecules from the MDDR, results are presented that explore these conformations and their ability to cover low-energy conformational space. © 2002 Wiley Periodicals, Inc. J Comput Chem 24: 10,20, 2003 [source] Scoring ligand similarity in structure-based virtual screeningJOURNAL OF MOLECULAR RECOGNITION, Issue 4 2009Maria I. Zavodszky Abstract Scoring to identify high-affinity compounds remains a challenge in virtual screening. On one hand, protein,ligand scoring focuses on weighting favorable and unfavorable interactions between the two molecules. Ligand-based scoring, on the other hand, focuses on how well the shape and chemistry of each ligand candidate overlay on a three-dimensional reference ligand. Our hypothesis is that a hybrid approach, using ligand-based scoring to rank dockings selected by protein,ligand scoring, can ensure that high-ranking molecules mimic the shape and chemistry of a known ligand while also complementing the binding site. Results from applying this approach to screen nearly 70,000 National Cancer Institute (NCI) compounds for thrombin inhibitors tend to support the hypothesis. EON ligand-based ranking of docked molecules yielded the majority (4/5) of newly discovered, low to mid-micromolar inhibitors from a panel of 27 assayed compounds, whereas ranking docked compounds by protein,ligand scoring alone resulted in one new inhibitor. Since the results depend on the choice of scoring function, an analysis of properties was performed on the top-scoring docked compounds according to five different protein,ligand scoring functions, plus EON scoring using three different reference compounds. The results indicate that the choice of scoring function, even among scoring functions measuring the same types of interactions, can have an unexpectedly large effect on which compounds are chosen from screening. Furthermore, there was almost no overlap between the top-scoring compounds from protein,ligand versus ligand-based scoring, indicating the two approaches provide complementary information. Matchprint analysis, a new addition to the SLIDE (Screening Ligands by Induced-fit Docking, Efficiently) screening toolset, facilitated comparison of docked molecules' interactions with those of known inhibitors. The majority of interactions conserved among top-scoring compounds for a given scoring function, and from the different scoring functions, proved to be conserved interactions in known inhibitors. This was particularly true in the S1 pocket, which was occupied by all the docked compounds. Copyright © 2009 John Wiley & Sons, Ltd. [source] ,tieredScreen' , Layered Virtual Screening Tool for the Identification of Novel Estrogen Receptor Alpha ModulatorsMOLECULAR INFORMATICS, Issue 5 2010Yidong Yang Abstract A novel tiered Structure-Based (SB) Virtual Screening (VS) workflow called tieredScreen was designed and implemented. The automated protocol utilises diverse computational tools in a synergistic manner to reduce false positives and increase the likelihood of converging on putative active molecules. The performance of the novel VS workflow was validated using the Directory of Useful Decoys (DUD) Estrogen Receptor , (ER,) antagonist dataset, and successfully deployed for the identification of novel antagonists of ER, from a screening collection of ca. 160,000 commercially available compounds. As well as yielding nanomolar (nM) active ligands identified previously through a docking only protocol, from a selection of eight virtual hits suggested by tieredScreen, four novel nM ER, binding chemotypes were identified and biologically validated , demonstrating the applicability of a tiered intervention for virtual screening. [source] Generation of Selective TACE Inhibitors: Ligand and Structure Based Molecular Modeling, Virtual Screening, Counter Pharmacophore Screening to Get Selective MoleculesMOLECULAR INFORMATICS, Issue 11-12 2009Malkeet, Singh Bahia Abstract This study describes the ligand based as well as structure based molecular modeling and virtual screening of selective tumor necrosis factor-, converting enzyme (TACE) inhibitors. In ligand based molecular modeling, two statistically reliable pharmacophore models HypoA1 and HypoB1 were generated using a same training set of 22,molecules. HypoA1,consists of two hydrogen bond acceptor and three hydrophobic groups whereas HypoB1 consists of one hydrogen bond donor, one ring aromatic and three hydrophobic groups. Virtual screening was performed with both models in in-house database of 1.2,million molecules. To remove non selective hits from screened molecules, a counter pharmacophore was generated using inhibitors of MMP-1, an important enzyme involved in musculoskeletal degradation. In structure based molecular modeling, docking analysis was performed to explore the important interactions between ligands and protein. On comparison, HypoA1 and HypoB1 were found to be complementing with results of docking analysis suggesting high reliability of both models for their use in virtual screening/designing of new molecules. [source] A Fragment-weighted Key-based Similarity Measure for Use in Structural Clustering and Virtual ScreeningMOLECULAR INFORMATICS, Issue 3 2006Marie Munk Jørgensen Abstract A new similarity measure and structural clustering method has been developed in which each structure is fragmented into ring systems, linkers, and side chains, and where the similarity between structures forms a weighted sum of the similarities between each set of fragments. We have applied the MACCS keys as molecular descriptors and identified a number of ways in which to improve the use of these keys for structural clustering and virtual screening. The method has been optimized to reproduce scaffold-biased clustering commonly used in medicinal chemistry. [source] An Efficient Method for the Synthesis of Peptide Aldehyde Libraries Employed in the Discovery of Reversible SARS Coronavirus Main Protease (SARS-CoV Mpro) InhibitorsCHEMBIOCHEM, Issue 7 2006Samer I. Al-Gharabli Dr. Abstract A method for the parallel solid-phase synthesis of peptide aldehydes has been developed. Protected amino acid aldehydes obtained by the racemization-free oxidation of amino alcohols with Dess,Martin periodinane were immobilized on threonyl resins as oxazolidines. Following Boc protection of the ring nitrogen to yield the N-protected oxazolidine linker, peptide synthesis was performed efficiently on this resin. A peptide aldehyde library was designed for targeting the SARS coronavirus main protease, SARS-CoV Mpro(also known as 3CLpro), on the basis of three different reported binding modes and supported by virtual screening. A set of 25 peptide aldehydes was prepared by this method and investigated in inhibition assays against SARS-CoV Mpro. Several potent inhibitors were found with IC50 values in the low micromolar range. An IC50 of 7.5 ,M was found for AcNSTSQ-H and AcESTLQ-H. Interestingly, the most potent inhibitors seem to bind to SARS-CoV Mpro in a noncanonical binding mode. [source] New Inhibitors of the Tat,TAR RNA Interaction Found with a "Fuzzy" Pharmacophore ModelCHEMBIOCHEM, Issue 6 2005Steffen Renner Dipl.-Biol. Abstract TAR RNA is a potential target for AIDS therapy. Ligand-based virtual screening was performed to retrieve novel scaffolds for RNA-binding molecules capable of inhibiting the Tat,TAR interaction, which is essential for HIV replication. We used a "fuzzy" pharmacophore approach (SQUID) and an alignment-free pharmacophore method (CATS3D) to carry out virtual screening of a vendor database of small molecules and to perform "scaffold-hopping". A small subset of 19 candidate molecules were experimentally tested for TAR RNA binding in a fluorescence resonance energy transfer (FRET) assay. Both methods retrieved molecules that exhibited activities comparable to those of the reference molecules acetylpromazine and chlorpromazine, with the best molecule showing ten times better binding behavior (IC50=46 ,M). The hits had molecular scaffolds different from those of the reference molecules. [source] Stabilization of G-Quadruplex DNA with Platinum(II) Schiff Base Complexes: Luminescent Probe and Down-Regulation of c- myc Oncogene ExpressionCHEMISTRY - A EUROPEAN JOURNAL, Issue 47 2009Peng Wu Dr. Abstract The interactions of a series of platinum(II) Schiff base complexes with c- myc G-quadruplex DNA were studied. Complex [PtL1a] (1,a; H2L1a=N,N,-bis(salicylidene)-4,5-methoxy-1,2-phenylenediamine) can moderately inhibit c- myc gene promoter activity in a cell-free system through stabilizing the G-quadruplex structure and can inhibit c- myc oncogene expression in cultured cells. The interaction between 1,a and G-quadruplex DNA has been examined by 1H NMR spectroscopy. By using computer-aided structure-based drug design for hit-to-lead optimization, an in silico G-quadruplex DNA model has been constructed for docking-based virtual screening to develop new platinum(II) Schiff base complexes with improved inhibitory activities. Complex [PtL3] (3; H2L3=N,N,-bis{4-[1-(2-propylpiperidine)oxy]salicylidene}-4,5-methoxy-1,2-phenylenediamine) has been identified with a top score in the virtual screening. This complex was subsequently prepared and experimentally tested in vitro for its ability to stabilize or induce the formation of the c -myc G-quadruplex. The inhibitory activity of 3 (IC50=4.4,,M) is tenfold more than that of 1,a. The interaction between 1,a or 3 with c- myc G-quadruplex DNA has been examined by absorption titration, emission titration, molecular modeling, and NMR titration experiments, thus revealing that both 1,a and 3 bind c- myc G-quadruplex DNA through an external end-stacking mode at the 3' terminal face of the G-quadruplex. Such binding of G-quadruplex DNA with 3 is accompanied by up to an eightfold increase in the intensity of photoluminescence at ,max=652,nm. Complex 3 also effectively down-regulated the expression of c- myc in human hepatocarcinoma cells. [source] Hit Identification and Biological Evaluation of Anticancer Pyrazolopyrimidines Endowed with Anti-inflammatory ActivityCHEMMEDCHEM, Issue 8 2010Stefano Alcaro Prof. Inhibiting COX: A small library of pyrazolopyriminines endowed with antiproliferative action was submitted to virtual screening against two COX isoforms. Three compounds were identified in silico as potentially selective COX-2 inhibitors. The biological assay confirmed one of them to be a COX-2 inhibitor with potency and selectivity comparable to known drugs. [source] | ||||||||||