Pharmacophore-based virtual screening to aid in the identification of unknown protein function

Chemical Biology & Drug Design
Prema L MallipeddiJames M Briggs

Abstract

A pharmacophore-based virtual screening method was developed and validated for use in predicting the function of a novel protein in terms of small metabolite binding. Five test cases were used for the validation study which spanned two different folds, four superfamilies, and three enzyme classes. Binding sites were predicted using a combination of two methods (CASTp and THEMATICS). The binding site was mapped with chemical probes representing hydrogen-bond donor, acceptor, negative ionizable, positive ionizable, and hydrophobe. The interaction maps were converted to three or four feature pharmacophore models and used to search a database containing 80 018 tautomers/protomers/conformers of 10 535 metabolites. The pharmacophore-based virtual screening eliminated >92% of the database as potential substrates and retrieved specific hits, which were ranked using a physics-based scoring function. The known substrate or product was ranked within the top 0.7% and substrate-like compounds within the top 1% of the metabolite database for all of the five test cases. The results suggest that using this pharmacophore-based virtual screening is a time-efficient strategy that can be applied to screen large databases to help predict the functi...Continue Reading

References

Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
Aug 15, 1998·Journal of Molecular Graphics & Modelling·M HendlichG Barnickel
Feb 27, 1999·Protein Science : a Publication of the Protein Society·A DalbyJ A Littlechild
Dec 11, 1999·Nucleic Acids Research·H M BermanP E Bourne
Jun 8, 2000·Journal of Medicinal Chemistry·H A CarlsonJ A McCammon
Oct 19, 2001·Proceedings of the National Academy of Sciences of the United States of America·M J OndrechenD Ringe
Dec 26, 2001·Nucleic Acids Research·Susumu GotoMinoru Kanehisa
Jun 13, 2002·Proceedings of the National Academy of Sciences of the United States of America·Dong Hae ShinSung-Hou Kim
Aug 22, 2002·Journal of Computer-aided Molecular Design·Sally A HindleThomas Lengaue
Sep 6, 2002·Journal of Medicinal Chemistry·Yvonne C MartinLinda M Traphagen
Jun 1, 1964·Biochimica Et Biophysica Acta·F WOLD, R BARKER
Dec 3, 2003·Journal of Structural and Functional Genomics·Sung-Hou KimRosalind Kim
Jul 29, 2004·Carbohydrate Research·Yanbin PanZhongwu Guo
Aug 4, 2004·Current Opinion in Chemical Biology·Johanna M Jansen, Eric J Martin
Nov 24, 2005·Proteins·Fabian GlaserJanet M Thornton
Feb 8, 2006·FEBS Letters·Csaba Hetényi, David van der Spoel
Nov 14, 2006·Nucleic Acids Research·Derek WilsonJulian Gough
Dec 7, 2006·Journal of the American Chemical Society·Johannes C HermannBrian K Shoichet
Apr 12, 2007·PLoS Biology·Abdellah Allali-HassaniCheryl H Arrowsmith
Jun 6, 2007·Nature Structural & Molecular Biology·Brian W Matthews
Jun 29, 2007·Bioinformation·Michal BrylinskiIrena Roterman
Jul 3, 2007·Nature·Johannes C HermannFrank M Raushel
Jul 3, 2007·Nature Chemical Biology·Ling SongJohn A Gerlt
Dec 13, 2007·Structure·John C Norvell, Jeremy M Berg
Jan 1, 2008·Proceedings of the National Academy of Sciences of the United States of America·Michal Brylinski, Jeffrey Skolnick
Apr 9, 2008·Current Medicinal Chemistry·Hongma Sun
Oct 18, 2011·Biochemistry·John A GerltJonathan V Sweedler

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Citations

May 23, 2013·Omics : a Journal of Integrative Biology·Vinay RandhawaGanesh Bagler
Apr 24, 2015·Frontiers in Plant Science·Mario SerranoChristian Meesters
Mar 14, 2017·The Journal of Steroid Biochemistry and Molecular Biology·Katharina R BeckAlex Odermatt

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