Docking Ligands into Flexible and Solvated Macromolecules. 2. Development and Application of Fitted 1.5 to the Virtual Screening of Potential HCV Polymerase Inhibitors

HCV NS5B polymerase is a validated target for the treatment of hepatitis C, known to be one of the most challenging enzymes for docking programs. In order to improve the low accuracy of existing docking methods observed with this challenging enzyme, we have significantly modified and updated F itted 1.0, a recently reported docking program, into F itted 1.5. This enhanced version is now applicable to the virtual screening of compound libraries and includes new features such as filters and pharmacophore- or interaction-site-oriented docking. As a first validation, F itted 1.5 was applied to the testing set previously developed for F itted 1.0 and extended to include hepatitis C virus (HCV) polymerase inhibitors. This first validation showed an increased accuracy as well as an increase in speed. It also shows that the accuracy toward HCV polymerase is better than previously observed with other programs. Next, application of F itted 1.5 to the virtual screening of the Maybridge library seeded with known HCV polymerase inhibitors revealed its ability to recover most of these actives in the top 5% of the hit list. As a third validation, further biological assays uncovered HCV polymerase inhibition for selected Maybridge compounds ranked in the top of the hit list.

[1]  Meitian Wang,et al.  Non-nucleoside inhibitors binding to hepatitis C virus NS5B polymerase reveal a novel mechanism of inhibition. , 2006, Journal of molecular biology.

[2]  L. Seeff,et al.  Aasld Practice Guideline Diagnosis, Management, and Treatment of Hepatitis C , 2003 .

[3]  Stephen Hanessian,et al.  A method for induced-fit docking, scoring, and ranking of flexible ligands. Application to peptidic and pseudopeptidic beta-secretase (BACE 1) inhibitors. , 2006, Journal of medicinal chemistry.

[4]  Christopher R. Corbeil,et al.  Docking Ligands into Flexible and Solvated Macromolecules, 1. Development and Validation of FITTED 1.0 , 2007, J. Chem. Inf. Model..

[5]  J. G. Park,et al.  FlexE ensemble docking approach to virtual screening for CDK2 inhibitors , 2007 .

[6]  Richard Nugent,et al.  Inhibitors of HCV NS5B polymerase. Part 2: Evaluation of the northern region of (2Z)-2-benzoylamino-3-(4-phenoxy-phenyl)-acrylic acid. , 2005, Bioorganic & medicinal chemistry letters.

[7]  Brian K. Shoichet,et al.  ZINC - A Free Database of Commercially Available Compounds for Virtual Screening , 2005, J. Chem. Inf. Model..

[8]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. , 2001, Advanced drug delivery reviews.

[9]  Claudio N. Cavasotto,et al.  Ligand docking and structure-based virtual screening in drug discovery. , 2007, Current topics in medicinal chemistry.

[10]  Uwe Koch,et al.  Interdomain Communication in Hepatitis C Virus Polymerase Abolished by Small Molecule Inhibitors Bound to a Novel Allosteric Site* , 2005, Journal of Biological Chemistry.

[11]  Christopher R. Corbeil,et al.  Towards the development of universal, fast and highly accurate docking/scoring methods: a long way to go , 2008, British journal of pharmacology.

[12]  Didier Rognan,et al.  ConsDock: A new program for the consensus analysis of protein–ligand interactions , 2002, Proteins.

[13]  Nicolas Moitessier,et al.  Combining pharmacophore search, automated docking, and molecular dynamics simulations as a novel strategy for flexible docking. Proof of concept: docking of arginine-glycine-aspartic acid-like compounds into the alphavbeta3 binding site. , 2004, Journal of medicinal chemistry.

[14]  Denis Labrecque,et al.  Discovery of thiophene-2-carboxylic acids as potent inhibitors of HCV NS5B polymerase and HCV subgenomic RNA replication. Part 2: tertiary amides. , 2004 .

[15]  Noriaki Hirayama,et al.  Ph4Dock: pharmacophore-based protein-ligand docking. , 2004, Journal of medicinal chemistry.

[16]  Thomas Lengauer,et al.  FlexE: efficient molecular docking considering protein structure variations. , 2001, Journal of molecular biology.

[17]  Maria Kontoyianni,et al.  Evaluation of library ranking efficacy in virtual screening , 2005, J. Comput. Chem..

[18]  Sandrine Gerber-Lemaire,et al.  Evaluation of docking programs for predicting binding of Golgi α‐mannosidase II inhibitors: A comparison with crystallography , 2007, Proteins.

[19]  Meitian Wang,et al.  Crystal Structures of the RNA-dependent RNA Polymerase Genotype 2a of Hepatitis C Virus Reveal Two Conformations and Suggest Mechanisms of Inhibition by Non-nucleoside Inhibitors* , 2005, Journal of Biological Chemistry.

[20]  Junmei Wang,et al.  Development and testing of a general amber force field , 2004, J. Comput. Chem..

[21]  David Haigh,et al.  Identification of GSK625433: A novel clinical candidate for the treatment of hepatitis C. , 2007 .

[22]  Boris Feld,et al.  Design and Synthesis of 3,4‐Dihydro‐1H‐[1]‐benzothieno[2,3‐c]pyran and 3,4‐Dihydro‐1H‐pyrano[3,4‐b]benzofuran Derivatives as Non‐Nucleoside Inhibitors of HCV NS5B RNA Dependent RNA Polymerase. , 2006 .

[23]  Hui Li,et al.  Identification and structure-based optimization of novel dihydropyrones as potent HCV RNA polymerase inhibitors. , 2006, Bioorganic & medicinal chemistry letters.

[24]  Chris Oostenbrink,et al.  Catalytic site prediction and virtual screening of cytochrome P450 2D6 substrates by consideration of water and rescoring in automated docking. , 2006, Journal of medicinal chemistry.

[25]  Darius Bilimoria,et al.  Discovery of thiophene-2-carboxylic acids as potent inhibitors of HCV NS5B polymerase and HCV subgenomic RNA replication. Part 2: tertiary amides. , 2004, Bioorganic & medicinal chemistry letters.

[26]  Paolo Bonvini,et al.  Identification of ellagic acid as potent inhibitor of protein kinase CK2: a successful example of a virtual screening application. , 2006, Journal of medicinal chemistry.

[27]  Meitian Wang,et al.  Non-nucleoside Analogue Inhibitors Bind to an Allosteric Site on HCV NS5B Polymerase , 2003, The Journal of Biological Chemistry.

[28]  Didier Rognan,et al.  Comparative evaluation of eight docking tools for docking and virtual screening accuracy , 2004, Proteins.

[29]  John Mao,et al.  Synthesis and pharmacokinetics of valopicitabine (NM283), an efficient prodrug of the potent anti-HCV agent 2'-C-methylcytidine. , 2006, Journal of medicinal chemistry.

[30]  C. E. Peishoff,et al.  A critical assessment of docking programs and scoring functions. , 2006, Journal of medicinal chemistry.

[31]  P. Hajduk,et al.  Discovering High-Affinity Ligands for Proteins: SAR by NMR , 1996, Science.

[32]  Stephen Hanessian,et al.  Docking of aminoglycosides to hydrated and flexible RNA. , 2006, Journal of medicinal chemistry.

[33]  Boris Feld,et al.  Discovery of pyrano[3,4-b]indoles as potent and selective HCV NS5B polymerase inhibitors. , 2004, Journal of medicinal chemistry.

[34]  Ezio Fornasiere,et al.  Valopicitabine dihydrochloride:a specific polymerase inhibitor of hepatitis C virus. , 2007, Current opinion in investigational drugs.