NOTE: This product is an add-on to ICM-Pro. This product also includes all the chemistry functionalities included in ICM-Chemist-Pro.

ICM Virtual Ligand Screening is a combination of the genuine internal coordinate docking methodology with a sophisticated global optimization scheme. Accurate and fast potentials and empirically adjusted scoring functions have led to an efficient virtual screening methodology in which ligands are fully and continuously flexible. The average yield of lead candidates is as high as 10% and in many cases only the top 1% of hits need to be tested experimentally to find a lead.

• fast and accurate docking and scoring procedure
• automatic incorporation of flexibility into the ligand and receptor
• index large .sdf files and get scripting access to large compound files
• from Smiles to 3D and from 3D to Smiles convertions
• use GUI to set up all stages of screening
• identify potential binding sites
• automatically convert your 2D database compounds to 3D, add hydrogens and assign charges
• dock large databases from chemical vendors or directly from MolCart
• template docking for pharmacophore based drug design
• dock on-the-fly Markush generated libraries and focused libraries
• apply additional selection criteria such as size, number of h-bond donors/acceptors/torsions
• scan substituted derivatives of your leads
• easy to use graphical user interface for post-docking analysis
• one-click hitlist generation, quickly browse through ligand binding poses
• browse scan results interactively with diverse display features such as hbond and mesh contact views
• analyze scan performance with score and property histograms

Three inhibitors discovered by the ICM virtual screening procedure. Activity was confirmed experimentally. The figure shows the active site of the protein in skin (molecular surface) representation, colored by binding properties: hydrophobic areas are in green, hydrogen bond donor areas are in blue and hydrogen bond acceptor areas are in red.

ICM-VLS Success Stories

ICM-VLS has been successfully applied to identify new leads for a number of targets by academic and industrial laboratories. Here is a list of some of the drug targets where ICM-VLS has identified inhibitors:

• GPCR - Melanin Concentrating Hormone [1]
• PDK1 [2]
• Ubiquitin-like pvirus proteinase [3]
• Alpha Antitrypsin [4]
• Serotonin N-acetyltransferase [5]
• EPhB2 [6]
• Androgen Receptor [7]
• Sirtuin [8]
• Enoyl Reductase [9]
• EGFR Tyrosine Kinase [10]
• TAR RNA [11]
• Thyroid Receptor [12]
• RAR [13]

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

"I had a tough case of tightly bound ligands in a crystal structure whose bound poses were difficult to reproduce with other programs. They could just not find the right pose - often, ICM fit it right into this tight site, with terrific overlap with much of the crystal structure pose.¿ Dr. Terry R. Stouch, PhD, Head, Computational Chemistry, Lexicon Pharmaceuticals

NOTE: Installation instructions for a linux cluster can be found here.