Inverse virtual screening of antitumor targets: pilot study on a small database of natural bioactive compounds.

An inverse virtual screening in silico approach has been applied to natural bioactive molecules to screen their efficacy against proteins involved in cancer processes, with the aim of directing future experimental assays. Docking studies were performed on a panel of 126 protein targets extracted from the Protein Data Bank, to analyze their possible interactions with a small library of 43 bioactive compounds. Analysis of the molecular docking results was performed through the use of tables containing energy data organized in a matrix. The application of this approach may facilitate the prediction of the activity of unknown ligands for known targets involved in the development of cancer and could be applied to other models based on different libraries of ligands and different panels of targets.

[1]  David S. Goodsell,et al.  Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function , 1998 .

[2]  Y.Z. Chen,et al.  Ligand–protein inverse docking and its potential use in the computer search of protein targets of a small molecule , 2001, Proteins.

[3]  Judith M. Rollinger,et al.  Accessing target information by virtual parallel screening—The impact on natural product research , 2009 .

[4]  Alan Talevi,et al.  A Combined Virtual Screening 2D and 3D QSAR Methodology for the Selection of New Anticonvulsant Candidates from a Natural Product Library , 2008 .

[5]  A. Ferrari,et al.  Novel 7-oxyiminomethyl derivatives of camptothecin with potent in vitro and in vivo antitumor activity. , 2001, Journal of medicinal chemistry.

[6]  F. Zunino,et al.  Synthesis and cytotoxic activity of substituted 7-aryliminomethyl derivatives of camptothecin. , 2004, European journal of medicinal chemistry.

[7]  A. Basile,et al.  Antibacterial and anticoagulant activities of coumarins isolated from the flowers of Magydaris tomentosa. , 2007, Planta medica.

[8]  L. Meijer,et al.  Inverse in silico screening for identification of kinase inhibitor targets. , 2007, Chemistry & biology.

[9]  E. Fattorusso,et al.  Sulcatin, a novel antiproliferative N-methylpyridinium alkaloid from the ascidian Microcosmus vulgaris. , 2000, Journal of natural products.

[10]  F. Zunino,et al.  Synthesis and cytotoxic activity of a new series of topoisomerase I inhibitors. , 2008, Bioorganic & medicinal chemistry letters.

[11]  J. T. Metz,et al.  Ligand efficiency indices as guideposts for drug discovery. , 2005, Drug discovery today.

[12]  Malin M. Young,et al.  Design, docking, and evaluation of multiple libraries against multiple targets , 2001, Proteins.

[13]  Y. Kashman,et al.  Decaryiol, a new cembrane diterpene from the marine soft coral Sarcophyton decaryi , 1981 .

[14]  E. Baker,et al.  Structure and inhibition of the human cell cycle checkpoint kinase, Wee1A kinase: an atypical tyrosine kinase with a key role in CDK1 regulation. , 2005, Structure.

[15]  A. Basile,et al.  Antimicrobial and Antioxidant Activities of Coumarins from the Roots of Ferulago campestris (Apiaceae) , 2009, Molecules.

[16]  B. Tursch,et al.  Chemical Studies of Marine Invertebrates ‐ XIII 2 ‐ Hydroxynephtenol, a Novel Cembrane Diterpene from the Soft Coral Litophyton Viridis (Coelenterata, Octocorallia, Alcyonacea) , 2010 .

[17]  Gisbert Schneider,et al.  Virtual screening: an endless staircase? , 2010, Nature Reviews Drug Discovery.

[18]  E. Fattorusso,et al.  Oxygenated cembranoids of the decaryiol type from the Indonesian soft coral Lobophytum sp. , 2009 .

[19]  C. Bokemeyer,et al.  Topotecan – A Novel Topoisomerase I Inhibitor: Pharmacology and Clinical Experience , 1999, Oncology.

[20]  O. Sticher,et al.  Coumarin Derivatives from Eryngium campestre1. , 1985, Planta medica.

[21]  A. Macho,et al.  Antitumor effects of two novel naturally occurring terpene quinones isolated from the Mediterranean ascidian Aplidium conicum. , 2005, Journal of medicinal chemistry.

[22]  David S. Goodsell,et al.  A semiempirical free energy force field with charge‐based desolvation , 2007, J. Comput. Chem..

[23]  T. Burke,et al.  Campthotecin Design and Delivery Approaches for Elevating Anti‐Topoisomerase I Activities in Vivo , 2000, Annals of the New York Academy of Sciences.

[24]  A. D. Rodrigues,et al.  3-Aminopyrrolidinone farnesyltransferase inhibitors: design of macrocyclic compounds with improved pharmacokinetics and excellent cell potency. , 2002, Journal of medicinal chemistry.

[25]  N. Paul,et al.  Recovering the true targets of specific ligands by virtual screening of the protein data bank , 2004, Proteins.

[26]  Ahmed Awad E. Ahmed,et al.  Monoterpene coumarins from Ferula ferulago. , 2001, Phytochemistry.

[27]  S. Dallavalle,et al.  First total synthesis of topopyrone C , 2007 .

[28]  Lance Stewart,et al.  The mechanism of topoisomerase I poisoning by a camptothecin analog , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[29]  T. Poulos,et al.  Heme-coordinating inhibitors of neuronal nitric oxide synthase. Iron-thioether coordination is stabilized by hydrophobic contacts without increased inhibitor potency. , 2010, Journal of the American Chemical Society.

[30]  Ik-Hwan Kim,et al.  Involvement of PKC and ROS in the cytotoxic mechanism of anti-leukemic decursin and its derivatives and their structure-activity relationship in human K562 erythroleukemia and U937 myeloleukemia cells. , 2005, Cancer letters.

[31]  Arthur J. Olson,et al.  AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading , 2009, J. Comput. Chem..

[32]  Fu Wei,et al.  Evaluation of various inverse docking schemes in multiple targets identification. , 2010, Journal of molecular graphics & modelling.

[33]  Xiaomin Luo,et al.  TarFisDock: a web server for identifying drug targets with docking approach , 2006, Nucleic Acids Res..

[34]  Theodora M. Steindl,et al.  Structure-based virtual screening for the discovery of natural inhibitors for human rhinovirus coat protein. , 2008, Journal of medicinal chemistry.