Protein interface pharmacophore mapping tools for small molecule protein: protein interaction inhibitor discovery.

Protein:protein interactions are becoming increasingly significant as potential drug targets; however, the rational identification of small molecule inhibitors of such interactions remains a challenge. Pharmacophore modelling is a popular tool for virtual screening of compound libraries, and has previously been successfully applied to the discovery of enzymatic inhibitors. However, the application of pharmacophore modelling in the field of protein:protein interaction inhibitors has historically been considered more of a challenge and remains limited. In this review, we explore the interaction mimicry by known inhibitors that originate from in vitro screening, demonstrating the validity of pharmacophore mapping in the generation of queries for virtual screening. We discuss the pharmacophore mapping methods that have been successfully employed in the discovery of first-in-class inhibitors. These successful cases demonstrate the usefulness of a "tool kit" of diverse strategies for application across a range of situations depending on the available structural information.

[1]  P. Svenningsson,et al.  Regulation of fibrinolysis by S100A10 in vivo. , 2011, Blood.

[2]  Marc De Maeyer,et al.  Structure based discovery of small molecule suppressors targeting bacterial lysozyme inhibitors. , 2011, Biochemical and biophysical research communications.

[3]  Z. Debyser,et al.  Fragment hopping approach directed at design of HIV IN-LEDGF/p75 interaction inhibitors , 2013, Journal of enzyme inhibition and medicinal chemistry.

[4]  C. Potten.  Radiation, the Ideal Cytotoxic Agent for Studying the Cell Biology of Tissues such as the Small Intestine1 , 2004, Radiation research.

[5]  Dragos Horvath,et al.  Pharmacophore-based virtual screening. , 2011, Methods in molecular biology.

[6]  T. Ganz,et al.  Decreased clearance of Pseudomonas aeruginosa from airways of mice deficient in lysozyme M , 2005, Journal of leukocyte biology.

[7]  Alexei Vazquez,et al.  The genetics of the p53 pathway, apoptosis and cancer therapy , 2008, Nature Reviews Drug Discovery.

[8]  David C Fry,et al.  Small-molecule inhibitors of protein-protein interactions: how to mimic a protein partner. , 2012, Current pharmaceutical design.

[9]  David Ryan Koes,et al.  PocketQuery: protein–protein interaction inhibitor starting points from protein–protein interaction structure , 2012, Nucleic Acids Res..

[10]  Philippe Roche,et al.  Chemical and structural lessons from recent successes in protein-protein interaction inhibition (2P2I). , 2011, Current opinion in chemical biology.

[11]  Saul H Rosenberg,et al.  Discovery of potent antagonists of the antiapoptotic protein XIAP for the treatment of cancer. , 2004, Journal of medicinal chemistry.

[12]  Ingo Muegge,et al.  Evaluation of docking/scoring approaches: A comparative study based on MMP3 inhibitors , 2000, J. Comput. Aided Mol. Des..

[13]  C. Chothia,et al.  The atomic structure of protein-protein recognition sites. , 1999, Journal of molecular biology.

[14]  Ji-won Park,et al.  Structural basis for the recognition of lysozyme by MliC, a periplasmic lysozyme inhibitor in Gram-negative bacteria. , 2009, Biochemical and biophysical research communications.

[15]  Jürgen Bajorath,et al.  Computational Methodologies for Compound Database Searching that Utilize Experimental Protein–Ligand Interaction Information , 2010, Chemical biology & drug design.

[16]  Zeger Debyser,et al.  HIV-1 Integrase Forms Stable Tetramers and Associates with LEDGF/p75 Protein in Human Cells* , 2003, The Journal of Biological Chemistry.

[17]  A. Levine,et al.  Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain , 1996, Science.

[18]  F. Kirchhoff,et al.  An optimized MM/PBSA virtual screening approach applied to an HIV‐1 gp41 fusion peptide inhibitor , 2011, Proteins.

[19]  Hsiao-Huei Wu,et al.  MDM2--master regulator of the p53 tumor suppressor protein. , 2000, Gene.

[20]  Steven Fletcher,et al.  Protein-protein interaction inhibitors: small molecules from screening techniques. , 2007, Current topics in medicinal chemistry.

[21]  Christopher L. McClendon,et al.  Reaching for high-hanging fruit in drug discovery at protein–protein interfaces , 2007, Nature.

[22]  A. Voet,et al.  Computational investigation of the HIV‐1 Rev multimerization using molecular dynamics simulations and binding free energy calculations , 2012, Proteins.

[23]  M. Hinds,et al.  Structural plasticity underpins promiscuous binding of the prosurvival protein A1. , 2008, Structure.

[24]  Ramaswamy Nilakantan,et al.  Discovery of novel inhibitors of the ZipA/FtsZ complex by NMR fragment screening coupled with structure-based design. , 2006, Bioorganic & medicinal chemistry.

[25]  A. Barabasi,et al.  An empirical framework for binary interactome mapping , 2008, Nature Methods.

[26]  Yong Cui,et al.  Using molecular simulations to probe pharmaceutical materials. , 2011, Journal of pharmaceutical sciences.

[27]  S. Ferro,et al.  Inhibition of the interaction between HIV-1 integrase and its cofactor LEDGF/p75: a promising approach in anti-retroviral therapy. , 2011, Mini reviews in medicinal chemistry.

[28]  Fabrizio Manetti,et al.  Identification of the first non-peptidic small molecule inhibitor of the c-Abl/14-3-3 protein-protein interactions able to drive sensitive and Imatinib-resistant leukemia cells to apoptosis. , 2010, Bioorganic & medicinal chemistry letters.

[29]  Peter Gruber,et al.  Modulators of protein-protein interactions: novel approaches in targeting protein kinases and other pharmaceutically relevant biomolecules. , 2011, Current topics in medicinal chemistry.

[30]  Garland R. Marshall,et al.  Three-dimensional structure of peptide—protein complexes: implications for recognition , 1992 .

[31]  Hyeong Jun An,et al.  Estimating the size of the human interactome , 2008, Proceedings of the National Academy of Sciences.

[32]  A. Voet,et al.  Guards of the great wall: bacterial lysozyme inhibitors. , 2012, Trends in microbiology.

[33]  Weihua Li,et al.  Insights into the interactions between HIV‐1 integrase and human LEDGF/p75 by molecular dynamics simulation and free energy calculation , 2008, Proteins.

[34]  Gerhard Klebe,et al.  DSX: A Knowledge-Based Scoring Function for the Assessment of Protein-Ligand Complexes , 2011, J. Chem. Inf. Model..

[35]  Jun Wang,et al.  Small-Molecule Inhibition of TNF-α , 2005, Science.

[36]  Jian Yu,et al.  PUMA regulates intestinal progenitor cell radiosensitivity and gastrointestinal syndrome. , 2008, Cell stem cell.

[37]  Julien Michel,et al.  Targeting the von Hippel–Lindau E3 Ubiquitin Ligase Using Small Molecules To Disrupt the VHL/HIF-1α Interaction , 2012, Journal of the American Chemical Society.

[38]  A. Hamilton,et al.  Strategies for targeting protein-protein interactions with synthetic agents. , 2005, Angewandte Chemie.

[39]  David Ryan Koes,et al.  Small-molecule inhibitor starting points learned from protein–protein interaction inhibitor structure , 2011, Bioinform..

[40]  Thierry Langer,et al.  LigandScout: 3-D Pharmacophores Derived from Protein-Bound Ligands and Their Use as Virtual Screening Filters , 2005, J. Chem. Inf. Model..

[41]  Giovanni Bottegoni,et al.  Protein-ligand docking. , 2011, Frontiers in bioscience.

[42]  C. Pannecouque,et al.  Tetrazolium-based colorimetric assay for the detection of HIV replication inhibitors: revisited 20 years later , 2008, Nature Protocols.

[43]  Timothy A. Springer,et al.  Structural basis for distinctive recognition of fibrinogen γC peptide by the platelet integrin αIIbβ3 , 2008, The Journal of cell biology.

[44]  V. Mikol,et al.  Crystal structures of the catalytic domain of HIV-1 integrase free and complexed with its metal cofactor: high level of similarity of the active site with other viral integrases. , 1998, Journal of molecular biology.

[45]  T. Berg.  Small-molecule inhibitors of protein-protein interactions. , 2008, Current opinion in drug discovery & development.

[46]  K. Audouze,et al.  Emerging classes of protein-protein interaction inhibitors and new tools for their development. , 2004, Current opinion in chemical biology.

[47]  Olivier Sperandio,et al.  Editorial: [Hot Topics: Toward the Design of Drugs on Protein-Protein Interactions] , 2012 .

[48]  Olivier Sperandio,et al.  Designing Focused Chemical Libraries Enriched in Protein-Protein Interaction Inhibitors using Machine-Learning Methods , 2010, PLoS Comput. Biol..

[49]  Ivet Bahar,et al.  Development of small-molecule PUMA inhibitors for mitigating radiation-induced cell death. , 2011, Current topics in medicinal chemistry.

[50]  T. Rush,et al.  Design and synthesis of indolo[2,3-a]quinolizin-7-one inhibitors of the ZipA-FtsZ interaction. , 2004, Bioorganic & medicinal chemistry letters.

[51]  Ariel Fernández,et al.  Wrapping mimicking in drug‐like small molecules disruptive of protein–protein interfaces , 2012, Proteins.

[52]  G. Klebe,et al.  Knowledge-based scoring function to predict protein-ligand interactions. , 2000, Journal of molecular biology.

[53]  Alba Chimirri,et al.  Inhibitors of the Interactions between HIV‐1 IN and the Cofactor LEDGF/p75 , 2011, ChemMedChem.

[54]  T. Rush,et al.  Combinatorial synthesis of substituted 3-(2-indolyl)piperidines and 2-phenyl indoles as inhibitors of ZipA-FtsZ interaction. , 2004, Bioorganic & medicinal chemistry.

[55]  Kam Y. J. Zhang,et al.  Pharmacophore modelling as a virtual screening tool for the discovery of small molecule protein-protein interaction inhibitors. , 2012, Current pharmaceutical design.

[56]  L. Donehower,et al.  Overexpression of Mdm2 in mice reveals a p53-independent role for Mdm2 in tumorigenesis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[57]  Jelle Hendrix,et al.  Overexpression of the Lens Epithelium-Derived Growth Factor/p75 Integrase Binding Domain Inhibits Human Immunodeficiency Virus Replication , 2006, Journal of Virology.

[58]  Yongqiang Zhu,et al.  Pharmacophore based drug design approach as a practical process in drug discovery. , 2010, Current computer-aided drug design.

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

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

[61]  R. Epaud,et al.  Bacterial Killing Is Enhanced by Expression of Lysozyme in the Lungs of Transgenic Mice1 , 2000, The Journal of Immunology.

[62]  Cristina Tintori,et al.  Targets Looking for Drugs: A Multistep Computational Protocol for the Development of Structure-Based Pharmacophores and Their Applications for Hit Discovery , 2008, J. Chem. Inf. Model..

[63]  Ó. Teijido,et al.  Upregulation of Bcl2 inhibits apoptosis‐driven BAX insertion but favors BAX relocalization in mitochondria , 2010, FEBS letters.

[64]  T. Korfhagen,et al.  Mouse lysozyme M is important in pulmonary host defense against Klebsiella pneumoniae infection. , 2004, American journal of respiratory and critical care medicine.

[65]  M. Botta,et al.  A New Nonpeptidic Inhibitor of 14-3-3 Induces Apoptotic Cell Death in Chronic Myeloid Leukemia Sensitive or Resistant to Imatinib , 2011, Journal of Pharmacology and Experimental Therapeutics.

[66]  Zeger Debyser,et al.  Small molecules targeting the interaction between HIV-1 integrase and LEDGF/p75 cofactor. , 2010, Bioorganic & medicinal chemistry.

[67]  Shuxing Zhang,et al.  Computer-aided drug discovery and development. , 2011, Methods in molecular biology.

[68]  P. D. de Boer,et al.  Genetic Analysis of the Escherichia coli FtsZ·ZipA Interaction in the Yeast Two-hybrid System , 2001, The Journal of Biological Chemistry.

[69]  R J Lynch,et al.  Non-peptide fibrinogen receptor antagonists. 1. Discovery and design of exosite inhibitors. , 1992, Journal of medicinal chemistry.

[70]  G. Mustata,et al.  Discovery of modulators of protein-protein interactions: current approaches and limitations. , 2011, Current topics in medicinal chemistry.

[71]  J. Becker,et al.  Spontaneous Immunity against Bcl-xL in Cancer Patients 1 , 2005, The Journal of Immunology.

[72]  A. Marchand,et al.  Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication. , 2010, Nature chemical biology.

[73]  Chan Li,et al.  Three-Dimensional Pharmacophore Design and Biochemical Screening Identifies Substituted 1,2,4-Triazoles as Inhibitors of the Annexin A2–S100A10 Protein Interaction , 2012, ChemMedChem.

[74]  Fabrizio Manetti,et al.  Small Molecule Inhibitors Targeting HIV‐1 Reverse Transcriptase Dimerization , 2008, Chembiochem : a European journal of chemical biology.

[75]  Andrew J. Wilson,et al.  Inhibition of protein-protein interactions using designed molecules. , 2009, Chemical Society reviews.

[76]  Ken Garber,et al.  Missing the target: ubiquitin ligase drugs stall. , 2005, Journal of the National Cancer Institute.

[77]  G. Verdine,et al.  The Challenge of Drugging Undruggable Targets in Cancer: Lessons Learned from Targeting BCL-2 Family Members , 2007, Clinical Cancer Research.

[78]  Didier Rognan,et al.  Ranking Targets in Structure-Based Virtual Screening of Three-Dimensional Protein Libraries: Methods and Problems , 2008, J. Chem. Inf. Model..

[79]  B. Hempstead,et al.  Annexin II regulates fibrin homeostasis and neoangiogenesis in vivo. , 2004, The Journal of clinical investigation.

[80]  Erinna F. Lee,et al.  Structure of the BH3 domains from the p53-inducible BH3-only proteins Noxa and Puma in complex with Mcl-1. , 2008, Journal of molecular biology.

[81]  W. L. Jorgensen,et al.  Small-molecule inhibitors of the interaction between the E3 ligase VHL and HIF1α. , 2012, Angewandte Chemie.

[82]  C G M Wilson,et al.  Small-molecule inhibitors of IL-2/IL-2R: lessons learned and applied. , 2011, Current topics in microbiology and immunology.

[83]  A. Voet,et al.  Fragment based drug design: from experimental to computational approaches. , 2012, Current medicinal chemistry.

[84]  Guy S. Salvesen,et al.  X-linked IAP is a direct inhibitor of cell-death proteases , 1997, Nature.

[85]  P A Kollman,et al.  Continuum solvent studies of the stability of RNA hairpin loops and helices. , 1998, Journal of biomolecular structure & dynamics.

[86]  M. Demetriou,et al.  Interleukin‐2, Interleukin‐7, T cell‐mediated autoimmunity, and N‐glycosylation , 2012, Annals of the New York Academy of Sciences.

[87]  P. Hajduk,et al.  SAR by NMR: putting the pieces together. , 2006, Molecular interventions.

[88]  A. Voet,et al.  De novo design of small molecule inhibitors targeting the LEDGF/p75-HIV integrase interaction , 2012 .

[89]  A. Engelman,et al.  Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[90]  Cristina Tintori,et al.  Computational studies of the interaction between the HIV‐1 integrase tetramer and the cofactor LEDGF/p75: Insights from molecular dynamics simulations and the Informational spectrum method , 2010, Proteins.

[91]  F. Bushman,et al.  Identification of a small-molecule binding site at the dimer interface of the HIV integrase catalytic domain. , 2001, Acta crystallographica. Section D, Biological crystallography.

[92]  Michelle R Arkin,et al.  Discovery of a potent small molecule IL-2 inhibitor through fragment assembly. , 2003, Journal of the American Chemical Society.

[93]  P. Zhou,et al.  Specific noncovalent interactions at protein-ligand interface: implications for rational drug design. , 2012, Current medicinal chemistry.

[94]  P. Colman,et al.  BCL-2 family antagonists for cancer therapy , 2008, Nature Reviews Drug Discovery.

[95]  Z. Debyser,et al.  Pharmacophore‐Based Discovery of Small‐Molecule Inhibitors of Protein–Protein Interactions between HIV‐1 Integrase and Cellular Cofactor LEDGF/p75 , 2009, ChemMedChem.

[96]  Olivier Sperandio,et al.  Rationalizing the chemical space of protein-protein interaction inhibitors. , 2010, Drug discovery today.

[97]  R. Hartmann,et al.  Prediction of protein-protein interaction inhibitors by chemoinformatics and machine learning methods. , 2007, Journal of medicinal chemistry.

[98]  A. Look,et al.  Slug Antagonizes p53-Mediated Apoptosis of Hematopoietic Progenitors by Repressing puma , 2005, Cell.

[99]  D. Fry.  Drug-like inhibitors of protein-protein interactions: a structural examination of effective protein mimicry. , 2008, Current protein & peptide science.

[100]  M. Yaffe,et al.  A Structural Basis for 14-3-3σ Functional Specificity*♦ , 2005, Journal of Biological Chemistry.

[101]  P. Goodford.  A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. , 1985, Journal of medicinal chemistry.

[102]  A. Voet,et al.  In search of second-generation HIV integrase inhibitors: targeting integration beyond strand transfer. , 2009, Future medicinal chemistry.

[103]  P. Kollman,et al.  Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models. , 2000, Accounts of chemical research.