Novel Strategy for Three-Dimensional Fragment-Based Lead Discovery

Fragment-based drug design (FBDD) is considered a promising approach in lead discovery. However, for a practical application of this approach, problems remain to be solved. Hence, a novel practical strategy for three-dimensional lead discovery is presented in this work. Diverse fragments with spatial positions and orientations retained in separately adjacent regions were generated by deconstructing well-aligned known inhibitors in the same target active site. These three-dimensional fragments retained their original binding modes in the process of new molecule construction by fragment linking and merging. Root-mean-square deviation (rmsd) values were used to evaluate the conformational changes of the component fragments in the final compounds and to identify the potential leads as the main criteria. Furthermore, the successful validation of our strategy is presented on the basis of two relevant tumor targets (CDK2 and c-Met), demonstrating the potential of our strategy to facilitate lead discovery against some drug targets.

[1]  Maurizio Pellecchia,et al.  A fragment-based approach for the discovery of isoform-specific p38? inhibitors , 2007 .

[2]  C. Lipinski.  Lead- and drug-like compounds: the rule-of-five revolution. , 2004, Drug discovery today. Technologies.

[3]  C. Meier,et al.  Discovery of 4-azaindoles as novel inhibitors of c-Met kinase. , 2009, Bioorganic & medicinal chemistry letters.

[4]  Mark Whittaker,et al.  The multiple roles of computational chemistry in fragment-based drug design , 2009, J. Comput. Aided Mol. Des..

[5]  M. Congreve,et al.  Recent developments in fragment-based drug discovery. , 2008, Journal of medicinal chemistry.

[6]  Marcel L Verdonk,et al.  Identification of inhibitors of protein kinase B using fragment-based lead discovery. , 2007, Journal of medicinal chemistry.

[7]  Michael M. Hann,et al.  RECAP-Retrosynthetic Combinatorial Analysis Procedure: A Powerful New Technique for Identifying Privileged Molecular Fragments with Useful Applications in Combinatorial Chemistry , 1998, J. Chem. Inf. Comput. Sci..

[8]  M. Congreve,et al.  Fragment-based lead discovery , 2004, Nature Reviews Drug Discovery.

[9]  Xiaohua Jiang,et al.  A fragment-based in situ combinatorial approach to identify high-affinity ligands for unknown binding sites. , 2010, Angewandte Chemie.

[10]  Maria Kontoyianni,et al.  Evaluation of docking performance: comparative data on docking algorithms. , 2004, Journal of medicinal chemistry.

[11]  Haiwei Song,et al.  Structural studies with inhibitors of the cell cycle regulatory kinase cyclin-dependent protein kinase 2. , 2002, Pharmacology & therapeutics.

[12]  H. Sakamoto,et al.  Discovery of 6-benzyloxyquinolines as c-Met selective kinase inhibitors. , 2010, Bioorganic & medicinal chemistry letters.

[13]  William L. Jorgensen,et al.  Journal of Chemical Information and Modeling , 2005, J. Chem. Inf. Model..

[14]  Stephen Green,et al.  Cyclin-dependent kinase 4 inhibitors as a treatment for cancer. Part 1: identification and optimisation of substituted 4,6-bis anilino pyrimidines. , 2003, Bioorganic & medicinal chemistry letters.

[15]  P. Hajduk,et al.  Puzzling through fragment-based drug design , 2006, Nature chemical biology.

[16]  Thelma Thompson,et al.  A new series of potent oxindole inhibitors of CDK2. , 2004, Bioorganic & medicinal chemistry letters.

[17]  Chong-Hwan Chang,et al.  Synthesis and evaluation of indenopyrazoles as cyclin-dependent kinase inhibitors. 3. Structure activity relationships at C3(1,2). , 2002, Journal of medicinal chemistry.

[18]  Angela Smallwood,et al.  Synthesis and evaluation of indenopyrazoles as cyclin-dependent kinase inhibitors. 3. Structure activity relationships at C3 , 2002 .

[19]  Chong-Hwan Chang,et al.  Synthesis and evaluation of indenopyrazoles as cyclin-dependent kinase inhibitors. Part 4: Heterocycles at C3. , 2004, Bioorganic & medicinal chemistry letters.

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

[21]  Anna Vulpetti,et al.  3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 1. Lead finding. , 2004, Journal of medicinal chemistry.

[22]  J. Murray,et al.  Triazolo[1,5-a]pyrimidines as novel CDK2 inhibitors: protein structure-guided design and SAR. , 2006, Bioorganic & medicinal chemistry letters.

[23]  Kerim Babaoglu,et al.  Deconstructing fragment-based inhibitor discovery , 2006, Nature chemical biology.

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

[25]  K. Rex,et al.  Discovery and optimization of potent and selective triazolopyridazine series of c-Met inhibitors. , 2009, Bioorganic & medicinal chemistry letters.

[26]  Jin-Jun Liu.  3,5,6‐Trisubstituted Naphthostyrils as CDK2 Inhibitors. , 2003 .

[27]  Terence Hui,et al.  SU9516: biochemical analysis of cdk inhibition and crystal structure in complex with cdk2. , 2003, Biochemical and biophysical research communications.

[28]  Anna Vulpetti,et al.  Benzodipyrazoles: a new class of potent CDK2 inhibitors. , 2005, Bioorganic & medicinal chemistry letters.

[29]  Wolfgang Jahnke,et al.  Second-site NMR screening and linker design. , 2003, Current topics in medicinal chemistry.

[30]  Andrew J. S. Knox,et al.  Integration of ligand and structure-based virtual screening for the identification of the first dual targeting agent for heat shock protein 90 (Hsp90) and tubulin. , 2009, Journal of medicinal chemistry.

[31]  S. Barelier,et al.  Fragment-based deconstruction of Bcl-xL inhibitors. , 2010, Journal of medicinal chemistry.

[32]  M. Drysdale,et al.  Discovery of a potent CDK2 inhibitor with a novel binding mode, using virtual screening and initial, structure-guided lead scoping. , 2007, Bioorganic & medicinal chemistry letters.

[33]  Michael Reggelin,et al.  Syntheses of novel 2,3-diaryl-substituted 5-cyano-4-azaindoles exhibiting c-Met inhibition activity. , 2009, Bioorganic & medicinal chemistry letters.

[34]  Tudor I. Oprea,et al.  Oncology exploration: charting cancer medicinal chemistry space. , 2006, Drug discovery today.

[35]  Daniel A Erlanson,et al.  Making drugs on proteins: site-directed ligand discovery for fragment-based lead assembly. , 2004, Current opinion in chemical biology.

[36]  Jeffrey Jie-Lou Liao,et al.  Molecular recognition of protein kinase binding pockets for design of potent and selective kinase inhibitors. , 2007, Journal of medicinal chemistry.

[37]  Anna Vulpetti,et al.  An analysis of the binding modes of ATP-competitive CDK2 inhibitors as revealed by X-ray structures of protein-inhibitor complexes. , 2005, Current medicinal chemistry. Anti-cancer agents.

[38]  S. Korsmeyer,et al.  An inhibitor of Bcl-2 family proteins induces regression of solid tumours , 2005, Nature.

[39]  L. Johnson,et al.  Protein kinase inhibition by staurosporine revealed in details of the molecular interaction with CDK2 , 1997, Nature Structural Biology.

[40]  Edward R Zartler,et al.  Fragonomics: fragment-based drug discovery. , 2005, Current opinion in chemical biology.

[41]  Wim G. J. Hol,et al.  In search of new lead compounds for trypanosomiasis drug design: A protein structure-based linked-fragment approach , 1992, J. Comput. Aided Mol. Des..

[42]  Peter M Fischer,et al.  Differential binding of inhibitors to active and inactive CDK2 provides insights for drug design. , 2006, Chemistry & biology.

[43]  K. Rex,et al.  c-Met Inhibitors with Novel Binding Mode Show Activity against Several Hereditary Papillary Renal Cell Carcinoma-related Mutations* , 2008, Journal of Biological Chemistry.

[44]  P. Hajduk,et al.  A decade of fragment-based drug design: strategic advances and lessons learned , 2007, Nature Reviews Drug Discovery.

[45]  G L Trainor,et al.  Quinazolines as cyclin dependent kinase inhibitors. , 2001, Bioorganic & medicinal chemistry letters.

[46]  S. Miknyoczki,et al.  Discovery of small molecule c-Met inhibitors: Evolution and profiles of clinical candidates. , 2010, Anti-cancer agents in medicinal chemistry.

[47]  A. Caflisch,et al.  Automatic and efficient decomposition of two-dimensional structures of small molecules for fragment-based high-throughput docking. , 2006, Journal of medicinal chemistry.

[48]  Chris Abell,et al.  Fragment-based approaches to enzyme inhibition. , 2007, Current opinion in biotechnology.

[49]  Robert Kiss,et al.  Virtual Fragment Docking by Glide: a Validation Study on 190 Protein-Fragment Complexes , 2010, J. Chem. Inf. Model..

[50]  J. Christensen,et al.  c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. , 2005, Cancer letters.

[51]  Alan Robertson,et al.  Structure-guided design of pyrazolo[1,5-a]pyrimidines as inhibitors of human cyclin-dependent kinase 2. , 2005, Bioorganic & medicinal chemistry letters.

[52]  M. Verdonk,et al.  Structure-guided fragment screening for lead discovery. , 2004, Current opinion in drug discovery & development.

[53]  Andrew Pannifer,et al.  Imidazo[1,2-b]pyridazines: a potent and selective class of cyclin-dependent kinase inhibitors. , 2004, Bioorganic & medicinal chemistry letters.

[54]  D. Kostrewa,et al.  Novel inhibitors of DNA gyrase: 3D structure based biased needle screening, hit validation by biophysical methods, and 3D guided optimization. A promising alternative to random screening. , 2000, Journal of medicinal chemistry.

[55]  J. Breed,et al.  Imidazo[1,2-a]pyridines: a potent and selective class of cyclin-dependent kinase inhibitors identified through structure-based hybridisation. , 2003, Bioorganic & medicinal chemistry letters.

[56]  M. Noble,et al.  Dissecting the determinants of cyclin-dependent kinase 2 and cyclin-dependent kinase 4 inhibitor selectivity. , 2006, Journal of medicinal chemistry.

[57]  K. Rex,et al.  Discovery and optimization of triazolopyridazines as potent and selective inhibitors of the c-Met kinase. , 2008, Journal of medicinal chemistry.

[58]  Stephen Green,et al.  Cyclin-dependent kinase 4 inhibitors as a treatment for cancer. Part 2: identification and optimisation of substituted 2,4-bis anilino pyrimidines. , 2003, Bioorganic & medicinal chemistry letters.

[59]  Kavita Shah,et al.  Corrigendum to “Discovery and optimization of potent and selective triazolopyridazine series of c-Met inhibitors” [Bioorg. Med. Chem. Lett. 19 (2009) 6307] , 2010 .

[60]  A. Osnowski,et al.  2-Anilino-4-(thiazol-5-yl)pyrimidine CDK inhibitors: synthesis, SAR analysis, X-ray crystallography, and biological activity. , 2004, Journal of medicinal chemistry.