Virtual Ligand Screening Success Stories

Recent success stories include identification of lead compounds for proteins including kinases (Cavasotto et al 2006), GPCRs (Katritch et al 2010 and Cavasotto et al 2008) nuclear receptors (Schapira et al 2003a and 2003b), proteases (Katrich et al 2007), transferases (Szewczuk et al 2007), HIV targets (Filikov et al 2000), and many others (Hayashi et al 2007, Mallya et ak 2007, Chrencik et al 2007, Bisson et al 2007, Outeiro et al 2007, Nicola et al 2007). In these cases the ICM-Virtual Ligand Screening (VLS) software was used to screen large compound databases into a receptor and score the hits based on predicted binding. The compounds were then tested experimentally; in most cases only a few dozen compounds were tested in order to find a hit resulting in a high enrichment factor. Many of these success stories were against difficult targets such as GPCRs where a Xray structure is not available, kinases where there is significant flexibility in the receptor upon ligand binding, or targeting protein-protein interfaces.

ICM-VLS has also been ranked the best virtual screening tool in comparisons reported by The Scripps Research Institute (Bursulaya et al 2003) and Astra Zeneca (Chen et al 2006). ICM-VLS performed the best in terms of predicting the ligand pose and enrichment factor (number of compounds you need to test experimentally to find a hit) compared to a selection of other commercially available screening algorithms.

Selected ICM-VLS Success Stories

Drug Target	Notes	Reference (see Publications section for full citation)
Pancreatic endoplasmic reticulum kinase	Specific inhibitors identified by ICM-VLS.	Wang H. et al. (2010)
P300 HAT	Screened 500K compounds – selected 194 for experimental testing resulting in 3 inhibitors which had specificity.	Bowers, E.M. et al. (2010)
GPCR – Adenosine A2A	Out of 56 compounds sent for experimental testing in functional assays. 23 compounds were identified with affinity <10 µM and 11 of those had had sub-µM affinities and 2 had affinities <60nM representing a diverse and novel set of antagonist scaffolds.	Katritch, V. et al. (2010)
TNF-Alpha	Structure-based discovery of natural-product-like inhibitors.	Chan, D.S. et al. (2010)
Ricin Toxin	Identification of new classes of ricin toxin inhibitors.	Bai Y. et al. (2010)
Tumor maker, AKR1B10	Discovery of several chomene-3carboxamide derivatives as potent competitive inhibitors.	Endo S. et al. (2010)
Dynamin I and II GTPase	Pthaladyns active compounds discovered using ICM-VLS to a homology model.	Odell LR et al. (2010)
H5N1 Neuraminidase	Used MolSoft’s ICMPocketFinder to identify a new pocket conformation. Used ICM-VLS to identify a ligand with different binding pose and interactions than oseltamivir and zanamivir.	An, J. et al. (2009)
Aryl Hydrocarbon Receptor	Discovery of a new class of inhibitors.	Bisson W.H. et al. (2009)
PTPN22	Sub and low micormolar inhibitors discovered using ICM-VLS scoring.	Wu S. et al. (2009)
Thermolysin	NCI compound library screened and 12 inibitors discovered.	Khan MTH et al. (2009)
GPCR-  Melanin Concentrating Hormone	First demonstration that GPCR models can be used for antagonist discovery by virtual screening.	Cavasotto, C.N. et al. (2008)
Ubiquitin-like Poxvirus Proteinase	230,000 available ketone and aldehyde compounds were screened. Out of 456 predicted ligands, 97 inhibitors of I7L proteinase activity were confirmed in biochemical assays.	Katritch, V. et al. (2007)
SARS Protease	In silico predictionof SARS protease inhibitors by ICM-VLS.	Plewczynski D et al. (2007)
Alpha Antitrypsin	Virtual ligand screening was performed on 1.2 million small molecules and 6 antagonists were identified which were further optimized using ICM tools.	Mallya, M. et al. (2007)
Serotonin N-acetyltransferase	1.2 million compounds were screened and 241 compounds tested resulting in the discovery of a new class of inhibitors.	Szewczuk, L.M. et al. (2007)
Androgen Receptor	Screening to multiple receptor conformations of the androgen receptor led to the identification of an antagonist.	Bisson, W.H. et al. (2007)
Enoyl Reductase	ChemBridge database was screened. 169 compounds were tested experimentally and 16 compounds had activity.	Nicola, G. et al. (2007)
EGFR Tyrosine Kinase	300K compounds were screened > 7 micromolar hits identified.	Cavasotto, C.N. et al. (2006)
Thyroid Receptor	250K compounds were screened, 75 were tested experimentally and 14 antagonists were discovered.	Schapira, M. et al. (2003)
RAR	Example of successful virtual screen to a homology model.	Schapira, M. et al. (2003)
TAR RNA	High enrichment factor and 7 new inhibitors identified.	Filikov, A.V. et al. (2000)

References

[1] Cavasotto CN, Orry AJ, Murgolo NJ, Czarniecki MF, Kocsi SA, Hawes BE, O'Neill KA, Hine H, Burton MS, Voigt JH, Abagyan RA, Bayne ML, Monsma FJ Jr.
Discovery of Novel Chemotypes to a G-Protein-Coupled Receptor through Ligand-Steered Homology Modeling and Structure-Based Virtual Screening. J Med Chem. 2008 Jan 17; [Epub ahead of print]

[2] Hayashi T, Mo JH, Gong X, Rossetto C, Jang A, Beck L, Elliott GI, Kufareva I, Abagyan R, Broide DH, Lee J, Raz E.
3-Hydroxyanthranilic acid inhibits PDK1 activation and suppresses experimental asthma by inducing T cell apoptosis. Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18619-24.

[3] Katritch V, Byrd CM, Tseitin V, Dai D, Raush E, Totrov M, Abagyan R, Jordan R, Hruby DE.
Discovery of small molecule inhibitors of ubiquitin-like poxvirus proteinase I7L using homology modeling and covalent docking approaches. J Comput Aided Mol Des. 2007 Oct-Nov;21(10-11):549-58.

[4] Mallya M, Phillips RL, Saldanha SA, Gooptu B, Brown SC, Termine DJ, Shirvani AM, Wu Y, Sifers RN, Abagyan R, Lomas DA.
Small molecules block the polymerization of Z alpha1-antitrypsin and increase the clearance of intracellular aggregates. J Med Chem. 2007 Nov 1;50(22):5357-63.

[5] Szewczuk LM, Saldanha SA, Ganguly S, Bowers EM, Javoroncov M, Karanam B, Culhane JC, Holbert MA, Klein DC, Abagyan R, Cole PA.
De novo discovery of serotonin N-acetyltransferase inhibitors. J Med Chem. 2007 Nov 1;50(22):5330-8.

[6] Chrencik JE, Brooun A, Recht MI, Nicola G, Davis LK, Abagyan R, Widmer H, Pasquale EB, Kuhn P.
Three-dimensional structure of the EphB2 receptor in complex with an antagonistic peptide reveals a novel mode of inhibition. J Biol Chem. 2007 Dec 14;282(50):36505-13.

[7] Bisson WH, Cheltsov AV, Bruey-Sedano N, Lin B, Chen J, Goldberger N, May LT, Christopoulos A, Dalton JT, Sexton PM, Zhang XK, Abagyan R.
Discovery of antiandrogen activity of nonsteroidal scaffolds of marketed drugs. Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):11927-32.

[8] Outeiro TF, Kontopoulos E, Altmann SM, Kufareva I, Strathearn KE, Amore AM, Volk CB, Maxwell MM, Rochet JC, McLean PJ, Young AB, Abagyan R, Feany MB, Hyman BT, Kazantsev AG.
Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease. Science. 2007 Jul 27;317(5837):516-9.

[9] Nicola G, Smith CA, Lucumi E, Kuo MR, Karagyozov L, Fidock DA, Sacchettini JC, Abagyan R.
Discovery of novel inhibitors targeting enoyl-acyl carrier protein reductase in Plasmodium falciparum by structure-based virtual screening. Biochem Biophys Res Commun. 2007 Jul 6;358(3):686-91.

[10] Cavasotto CN, Ortiz MA, Abagyan RA, Piedrafita FJ.
In silico identification of novel EGFR inhibitors with antiproliferative activity against cancer cells.
Bioorg Med Chem Lett. 2006 Jan 11

[11] Filikov, A.V., Mohan, V., Vickers, T.A., Griffey, R.H., Cook, P.D., Abagyan, R.A., and James, T.L.
Identification of Ligands For HIV-1 TAR RNA Via Structure Based Virtual Screening
JCAMD Aug 14(6), 593-610

[12] Schapira, M.,Raaka, B., Das, S., Fan, L., Totrov, M., Zhou, Z., Wilson, S., Abagyan, R. and Samuels, H.
Discovery of Diverse Thyroid Hormone Receptor Antagonists by High-Throughput Docking
PNAS 100(12), 7354-7359

[13] Schapira, M., Abagyan, R.A. and Totrov, M.M.
Nuclear Hormone Receptor Targeted Virtual Screening
J. Med. Chem. ASAP Article. 10.1021

[14] Katritch V, Jaakola VP, Lane JR, Lin J, Ijzerman AP, Yeager M, Kufareva I, Stevens RC, Abagyan R. Structure-based discovery of novel chemotypes for adenosine A(2A) receptor antagonists. J. Med. Chem. 2010 Feb 25;53(4):1799-809.

[15] Chan DS, Lee HM, Yang F, Che CM, Wong CC, Abagyan R, Leung CH, Ma DL.[15] Structure-Based Discovery of Natural-Product-like TNF-alpha Inhibitors. Angew Chem Int Ed Engl. 2010 Mar 16;49(16):2860-2864.

[16] Modeling of the aryl hydrocarbon receptor (AhR) ligand binding domain and its utility in virtual ligand screening to predict new AhR ligands. Bisson WH, Koch DC, O'Donnell EF, Khalil SM, Kerkvliet NI, Tanguay RL, Abagyan R, Kolluri SK. J. Med. Chem2009 Sep 24;52(18):5635-41