In-Silico Approaches to Multi-target Drug Discovery

Multi-target drugs against selective multiple targets improve therapeutic efficacy, safety and resistance profiles by collective regulations of a primary therapeutic target together with compensatory elements and resistance activities. Efforts have been made to employ in-silico methods for facilitating the search and design of selective multi-target agents. These methods have shown promising potential in facilitating drug discovery directed at selective multiple targets.

[1]  Susan O'Brien,et al.  Results of dasatinib therapy in patients with early chronic-phase chronic myeloid leukemia. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  G. Church,et al.  Identifying regulatory networks by combinatorial analysis of promoter elements , 2001, Nature Genetics.

[3]  Ming-Li Xiang,et al.  Pharmacophore Modelling and Virtual Screening for Identification of New Aurora‐A Kinase Inhibitors , 2008, Chemical biology & drug design.

[4]  C. Bacchi,et al.  Imatinib treatment for gastrointestinal stromal tumour (GIST) , 2009, Journal of cellular and molecular medicine.

[5]  Ram Samudrala,et al.  Novel paradigms for drug discovery: computational multitarget screening. , 2008, Trends in pharmacological sciences.

[6]  Richard Morphy,et al.  The physicochemical challenges of designing multiple ligands. , 2006, Journal of medicinal chemistry.

[7]  Marina Kriajevska,et al.  Combined treatment of bladder cancer cell lines with lapatinib and varying chemotherapy regimens--evidence of schedule-dependent synergy. , 2007, Urology.

[8]  Subhra Mohapatra,et al.  Roscovitine Inhibits Differentiation and Invasion in a Three-Dimensional Skin Reconstruction Model of Metastatic Melanoma , 2007, Molecular Cancer Research.

[9]  S. Ramamoorthy,et al.  Regulation of monoamine transporters: Influence of psychostimulants and therapeutic antidepressants , 2005, The AAPS Journal.

[10]  Adrian L Gill,et al.  A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. , 2007, Current topics in medicinal chemistry.

[11]  R. A. Etten,et al.  Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition , 2007, Nature Reviews Cancer.

[12]  Yan Tang,et al.  CHIR-258: A Potent Inhibitor of FLT3 Kinase in Experimental Tumor Xenograft Models of Human Acute Myelogenous Leukemia , 2005, Clinical Cancer Research.

[13]  Tooru Kimura,et al.  Structure of the aspartic protease plasmepsin 4 from the malarial parasite Plasmodium malariae bound to an allophenylnorstatine-based inhibitor. , 2006, Acta crystallographica. Section D, Biological crystallography.

[14]  Horvath Dragos,et al.  Predicting the predictability: a unified approach to the applicability domain problem of QSAR models. , 2009, Journal of chemical information and modeling.

[15]  Nick Holford,et al.  Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics. , 2006, Blood.

[16]  Luhua Lai,et al.  Discovery of multitarget inhibitors by combining molecular docking with common pharmacophore matching. , 2008, Journal of medicinal chemistry.

[17]  Yujia Dai,et al.  ABT-869, a multitargeted receptor tyrosine kinase inhibitor: inhibition of FLT3 phosphorylation and signaling in acute myeloid leukemia. , 2007, Blood.

[18]  Fabian Mörchen,et al.  Maximum Common Binding Modes (MCBM): Consensus Docking Scoring Using Multiple Ligand Information and Interaction Fingerprints , 2008, J. Chem. Inf. Model..

[19]  Ming-Chih Crouthamel,et al.  Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity , 2007, Molecular Cancer Therapeutics.

[20]  X. H. Liu,et al.  Virtual Screening of Abl Inhibitors from Large Compound Libraries by Support Vector Machines , 2009, J. Chem. Inf. Model..

[21]  M. Oechsner,et al.  COMT-inhibition increases serum levels of dihydroxyphenylacetic acid (DOPAC) in patients with advanced Parkinson's disease , 2002, Journal of Neural Transmission.

[22]  Ines Gockel,et al.  Co-expression of receptor tyrosine kinases in esophageal adenocarcinoma and squamous cell cancer. , 2008, Oncology reports.

[23]  S. Okabe,et al.  Characteristics of Dasatinib- and Imatinib-Resistant Chronic Myelogenous Leukemia Cells , 2008, Clinical Cancer Research.

[24]  Jia Jia,et al.  Comparative analysis of machine learning methods in ligand-based virtual screening of large compound libraries. , 2009, Combinatorial chemistry & high throughput screening.

[25]  N. Rahimi,et al.  IQGAP1-Dependent Signaling Pathway Regulates Endothelial Cell Proliferation and Angiogenesis , 2008, PloS one.

[26]  Felix Deanda,et al.  Kinase-Targeted Library Design through the Application of the PharmPrint Methodology , 2008, J. Chem. Inf. Model..

[27]  Pascal Furet,et al.  Antileukemic effects of the novel, mutant FLT3 inhibitor NVP-AST487: effects on PKC412-sensitive and -resistant FLT3-expressing cells. , 2008, Blood.

[28]  Z. R. Li,et al.  A support vector machines approach for virtual screening of active compounds of single and multiple mechanisms from large libraries at an improved hit-rate and enrichment factor. , 2008, Journal of molecular graphics & modelling.

[29]  Humberto González Díaz,et al.  Unified QSAR and network‐based computational chemistry approach to antimicrobials, part 1: Multispecies activity models for antifungals , 2008, J. Comput. Chem..

[30]  D. Sacks,et al.  IQGAP proteins are integral components of cytoskeletal regulation , 2003, EMBO reports.

[31]  Rolf Müller,et al.  Crosstalk of oncogenic and prostanoid signaling pathways , 2004, Journal of Cancer Research and Clinical Oncology.

[32]  M. Socinski,et al.  Vascular endothelial growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer: a review of recent clinical trials. , 2007, Reviews on recent clinical trials.

[33]  R. Gozalbes,et al.  Development and experimental validation of a docking strategy for the generation of kinase-targeted libraries. , 2008, Journal of medicinal chemistry.

[34]  D. Reardon,et al.  Targeting multiple kinases in glioblastoma multiforme , 2009 .

[35]  Lourdes Santana,et al.  Unified QSAR approach to antimicrobials. Part 2: predicting activity against more than 90 different species in order to halt antibacterial resistance. , 2007, Bioorganic & medicinal chemistry.

[36]  C. Seyfried,et al.  5-HT reuptake inhibitors with 5-HT(1B/1D) antagonistic activity: a new approach toward efficient antidepressants. , 2000, Journal of medicinal chemistry.

[37]  Humberto González-Díaz,et al.  Multi-target spectral moments for QSAR and Complex Networks study of antibacterial drugs. , 2009, European journal of medicinal chemistry.

[38]  B Xie,et al.  Synergistic therapeutic actions of herbal ingredients and their mechanisms from molecular interaction and network perspectives. , 2009, Drug discovery today.

[39]  Andreas Bender,et al.  "Bayes Affinity Fingerprints" Improve Retrieval Rates in Virtual Screening and Define Orthogonal Bioactivity Space: When Are Multitarget Drugs a Feasible Concept? , 2006, J. Chem. Inf. Model..

[40]  Thomas S. Lin,et al.  Flavopiridol in chronic lymphocytic leukemia: a concise review. , 2009, Clinical lymphoma & myeloma.

[41]  J. Brugge,et al.  Activity of the multikinase inhibitor dasatinib against ovarian cancer cells , 2009, British Journal of Cancer.

[42]  Hong Chang,et al.  CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. , 2004, Blood.

[43]  Jeffrey N. Myers,et al.  Sorafenib inhibits the angiogenesis and growth of orthotopic anaplastic thyroid carcinoma xenografts in nude mice , 2007, Molecular Cancer Therapeutics.

[44]  Christophe Massard,et al.  Phase II Study of Dasatinib in Patients with Metastatic Castration-Resistant Prostate Cancer , 2009, Clinical Cancer Research.

[45]  Sang Hoon Lee,et al.  In vivo Target Modulation and Biological Activity of CHIR-258, a Multitargeted Growth Factor Receptor Kinase Inhibitor, in Colon Cancer Models , 2005, Clinical Cancer Research.

[46]  Xin Huang,et al.  Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial , 2006, The Lancet.

[47]  I. Kopin,et al.  Monoamine oxidase and catecholamine metabolism. , 1994, Journal of neural transmission. Supplementum.

[48]  E. Sausville,et al.  Early induction of apoptosis in hematopoietic cell lines after exposure to flavopiridol. , 1998, Blood.

[49]  K. Shokat,et al.  Escape from HER family tyrosine kinase inhibitor therapy by the kinase inactive HER3 , 2007, Nature.

[50]  Ariel Fernández,et al.  Turning promiscuous kinase inhibitors into safer drugs. , 2008, Trends in biotechnology.

[51]  Jaffer A. Ajani,et al.  New Pharmacological Developments in the Treatment of Hepatocellular Cancer , 2012, Drugs.

[52]  Andreas Bender,et al.  Analysis of Activity Space by Fragment Fingerprints, 2D Descriptors, and Multitarget Dependent Transformation of 2D Descriptors , 2006, J. Chem. Inf. Model..

[53]  M. Millan Multi-target strategies for the improved treatment of depressive states: Conceptual foundations and neuronal substrates, drug discovery and therapeutic application. , 2006, Pharmacology & therapeutics.

[54]  D. Reardon,et al.  Targeting multiple kinases in glioblastoma multiforme. , 2009, Expert opinion on investigational drugs.

[55]  Christine Stephan,et al.  The RET kinase inhibitor NVP-AST487 blocks growth and calcitonin gene expression through distinct mechanisms in medullary thyroid cancer cells. , 2007, Cancer research.

[56]  Martin Krug,et al.  Recent advances in the development of multi-kinase inhibitors. , 2008, Mini reviews in medicinal chemistry.

[57]  A. Senderowicz,et al.  Flavopiridol: the First Cyclin-Dependent Kinase Inhibitor in Human Clinical Trials , 2004, Investigational New Drugs.

[58]  B. Druker,et al.  Sensitivity of oncogenic KIT mutants to the kinase inhibitors MLN518 and PD180970. , 2004, Blood.

[59]  M. Gordon,et al.  Sunitinib versus Interferon Alfa in Metastatic Renal-Cell Carcinoma , 2008 .

[60]  P. Blier,et al.  Prospect of a dopamine contribution in the next generation of antidepressant drugs: the triple reuptake inhibitors. , 2009, Current drug targets.

[61]  G. Sonpavde,et al.  Pazopanib, a potent orally administered small-molecule multitargeted tyrosine kinase inhibitor for renal cell carcinoma , 2008, Expert opinion on investigational drugs.

[62]  Eugenio Uriarte,et al.  Alignment-free prediction of a drug-target complex network based on parameters of drug connectivity and protein sequence of receptors. , 2009, Molecular pharmaceutics.

[63]  Christopher M. Overall,et al.  Validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy , 2006, Nature Reviews Cancer.

[64]  M. Verdonk,et al.  A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. , 2007, Current topics in medicinal chemistry.

[65]  Richard Morphy,et al.  The influence of target family and functional activity on the physicochemical properties of pre-clinical compounds. , 2006, Journal of medicinal chemistry.

[66]  Xiaohua Ma,et al.  Mechanisms of drug combinations: interaction and network perspectives , 2009, Nature Reviews Drug Discovery.

[67]  R. Shank,et al.  Pyrroloisoquinoline antidepressants. 2. In-depth exploration of structure-activity relationships. , 1987, Journal of medicinal chemistry.

[68]  M. Baccarani,et al.  Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. , 2002, The New England journal of medicine.

[69]  Boon Chuan Low,et al.  Evaluation of Virtual Screening Performance of Support Vector Machines Trained by Sparsely Distributed Active Compounds , 2008, J. Chem. Inf. Model..

[70]  Gary K. Schwartz,et al.  A Phase II Study of Flavopiridol (Alvocidib) in Combination with Docetaxel in Refractory, Metastatic Pancreatic Cancer , 2009, Pancreatology.

[71]  K. Chou,et al.  Unified QSAR approach to antimicrobials. 4. Multi-target QSAR modeling and comparative multi-distance study of the giant components of antiviral drug-drug complex networks. , 2009, Bioorganic & medicinal chemistry.

[72]  S. Sherman,et al.  Early clinical studies of novel therapies for thyroid cancers. , 2008, Endocrinology and metabolism clinics of North America.

[73]  Josep Tabernero,et al.  The Role of VEGF and EGFR Inhibition: Implications for Combining Anti–VEGF and Anti–EGFR Agents , 2007, Molecular Cancer Research.

[74]  S D Kemp,et al.  Potential mechanism for sustained antiretroviral efficacy of AZT-3TC combination therapy. , 1995, Science.

[75]  Peter J. Parker,et al.  HER2 Oncogenic Function Escapes EGFR Tyrosine Kinase Inhibitors via Activation of Alternative HER Receptors in Breast Cancer Cells , 2008, PloS one.

[76]  D. Sacks,et al.  IQGAP1 modulates activation of B-Raf , 2007, Proceedings of the National Academy of Sciences.

[77]  Barry Sloan,et al.  Pazopanib, a VEGF receptor tyrosine kinase inhibitor for cancer therapy. , 2008, Current opinion in investigational drugs.

[78]  Keith L. Ligon,et al.  Coactivation of Receptor Tyrosine Kinases Affects the Response of Tumor Cells to Targeted Therapies , 2007, Science.

[79]  Joanna Schwartz,et al.  Current combination chemotherapy regimens for metastatic breast cancer. , 2009, American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists.

[80]  Keith T Flaherty,et al.  Multiple signaling pathways must be targeted to overcome drug resistance in cell lines derived from melanoma metastases , 2006, Molecular Cancer Therapeutics.

[81]  出口 靖之,et al.  Comparison of imatinib, dasatinib, nilotinib and INNO-406 in imatinib-resistant cell lines , 2007 .

[82]  Brian Lord,et al.  In-vitro and in-vivo characterization of JNJ-7925476, a novel triple monoamine uptake inhibitor. , 2008, European journal of pharmacology.

[83]  N. Nitta,et al.  A combination of cisplatin-eluting gelatin microspheres and flavopiridol enhances anti-tumour effects in a rabbit VX2 liver tumour model. , 2010, The British journal of radiology.

[84]  S. Emanuel,et al.  The in vitro and in vivo effects of JNJ-7706621: a dual inhibitor of cyclin-dependent kinases and aurora kinases. , 2005, Cancer research.

[85]  Ignacio Wistuba,et al.  Inhibition of c-Src expression and activation in malignant pleural mesothelioma tissues leads to apoptosis, cell cycle arrest, and decreased migration and invasion , 2007, Molecular Cancer Therapeutics.

[86]  Brian K. Shoichet,et al.  Virtual screening of chemical libraries , 2004, Nature.

[87]  Yoshua Bengio,et al.  Collaborative Filtering on a Family of Biological Targets , 2006, J. Chem. Inf. Model..

[88]  David Bates,et al.  ZD-6474. AstraZeneca. , 2003, Current opinion in investigational drugs.

[89]  E. Vokes,et al.  Phase II study of flavopiridol in patients with advanced colorectal cancer. , 2003, Annals of oncology : official journal of the European Society for Medical Oncology.

[90]  B. Stockwell,et al.  Multicomponent therapeutics for networked systems , 2005, Nature Reviews Drug Discovery.

[91]  Ramadevi Sanam,et al.  Discovery of novel small-molecule inhibitors of human epidermal growth factor receptor-2: combined ligand and target-based approach. , 2008, Journal of medicinal chemistry.

[92]  Hans Briem,et al.  Classifying “Kinase Inhibitor‐Likeness” by Using Machine‐Learning Methods , 2005, Chembiochem : a European journal of chemical biology.

[93]  Jeffrey D. Goldsmith,et al.  Flt-1-Dependent Survival Characterizes the Epithelial-Mesenchymal Transition of Colonic Organoids , 2003, Current Biology.

[94]  S Fruehauf,et al.  Synergistic activity of imatinib and 17-AAG in imatinib-resistant CML cells overexpressing BCR-ABL – Inhibition of P-glycoprotein function by 17-AAG , 2005, Leukemia.

[95]  Neeraj Gupta,et al.  Phase I and biomarker study of ABT-869, a multiple receptor tyrosine kinase inhibitor, in patients with refractory solid malignancies. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[96]  G. Hortobagyi,et al.  Mechanisms of Disease: understanding resistance to HER2-targeted therapy in human breast cancer , 2006, Nature Clinical Practice Oncology.

[97]  Yujia Dai,et al.  Inhibition of phosphorylation of the colony-stimulating factor-1 receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and other tyrosine kinase inhibitors , 2006, Molecular Cancer Therapeutics.

[98]  Pero Melloni,et al.  POTENTIAL ANTIDEPRESSANT AGENTS. α-ARYLOXY-BENZYL DERIVATIVES OF ETHANOLAMINE AND MORPHOLINE , 1984 .

[99]  Lourdes Santana,et al.  Unify QSAR approach to antimicrobials. Part 1: predicting antifungal activity against different species. , 2006, Bioorganic & medicinal chemistry.