Research progress in protein-protein interactions and their inhibitors

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1 Chinese Bulletin of Life Sciences Vol. 19, No. 5 Oct., (2007) ( ) Q51 A Research progress in protein-protein interactions and their inhibitors ZHAO Yaxue, TANG Yun* (School of Pharmacy, East China University of Science and Technology, Shanghai , China) Abstract: Protein-protein interactions play important roles in a wide range of biological processes. Gene regulation, immune response, signal transduction, cellular architecture and many other mechanisms of cellular control are involved in the interactions of protein and protein. So the discovery of drugs that could prohibit protein-protein interactions has become a very active research field in recent years. However, it is full of challenge to design such inhibitors because of the unique properties of the protein-protein interfaces. For example, the interface is usually big and rather flat. In this review, we focused on the properties of proteinprotein interactions, the interactions between these properties and the design of inhibitors. Computational methods predicting protein-protein interactions as well as classification and features of inhibitors targeting protein-protein interactions were also discussed. At last, an example of how to design inhibitors to block bindings of protein and protein was given. Key words: protein-protein interaction; interface; inhibitor; design 30 8 [1] (Food and Drug Administration FDA) (new molecule entities NMEs) ( 1) ( ) (1982 ) ytang234@ecust.edu.cn (1968 ) *

2 FDA NMEs( fda.gov/cder/rdmt/default.htm) - [2] - - p53-hdm2 [3] - [4-5] 1 - ( ph ) Jones Thornton [6] Å Å 2 639Å Å 2 Lo Conte [7] 1600Å 2 52 (Absorption Distribution Metabolism Excretion Toxicity ADME/T) (hot spots) [8] 600Å 2 - Trp Tyr Arg [8] Sillerud Larson [9] - Pro Ile Tyr Trp Asp Arg - MM-PBSA (molecular mechanics-poisson-boltzmann surface area) (computational alanine scanning) MM-GBSA (molecular mechanics-generalized Born surface area) [10-12] PASS - [13] Kortemme Baker [14] [6] 1.3 -

3 [6] - 56% 29% 15% [15] 1.4 π-π π K D mol/l K D mol/l [16] Cochran [17] 2 I P 2 P 1 I P 2 P 2 I 2 Cochran [17] P 1 1 P 2 2 I K I K P [21] D-Dock [18] ZDOCK [19] Hex [20] HADDOCK [21] - - [22] - 80%

4 ( ) [23] 3.2 (structure-based drug design SBDD) (human immunodeficiency virus HIV) [24] Xu [25] - (credit-card) π-π Trosset [26] β - β- Tcf3/Tcf4 4 XIAP caspase-9 (caspase) caspase caspase caspase (inhibitors of apoptosis proteins IAPs) IAP (baculovirus IAP repeats domain BIR) caspase caspase IAP X- IAP(X-linked IAP XIAP) BIR (BIR3) caspase-9 [27] XIAP XIAP caspase-9 XIAP caspase IAP (Second mitochondria-derived activator of caspase or Direct IAP Binding With Low PI Smac/DIABLO) Smac caspase-9 XIAP [28-29]

5 Smac XIAP caspase XIAP Smac Smac N XIAP Liu [30] Smac 20- Smac 9- Smac XIAP 9- Smac XIAP Smac 9 N Ala Smac XIAP Val Pro Ile Ala Smac XIAP N AVPI (Ala Val Pro Ile) XIAP BIR3 XIAP G306 T308 E314 W323 XIAP Smac Wu [29] 3 Smac AVPI XIAP XIAP XIAP caspase-9 3 Smac AVPI XIAP 4.2 Smac N AVPI AVPI XIAP caspase-9 Kipp [31] AVPI XIAP Ala XIAP Ala XIAP Ala Val XIAP Pro Ile ARPF (Ala Arg Pro Phe) AVPF (Ala Val Pro Phe) Nikolovska-Coleska [32] ARPF AVPF [32] XIAP caspase-9 Wang Fesik Wang Ile XIAP 1 ( 4 ) Val Pro [27,33-34] Fesik AVPI XIAP NMR [35] XIAP caspase AVPI 1

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J Mol Biol, 1998, 280(1): 1-9 [9] Sillerud L O, Larson R S. Design and structure of peptide and peptidomimetic antagonists of protein-protein interaction. Curr Protein Pept Sci, 2005, 6(2): [10] Gohlke H, Kiel C, Case D A. Insights into protein-protein binding by binding free energy calculation and free energy decomposition for the Ras-Raf and Ras-RalGDS complexes. J Mol Biol, 2003, 330(4): [11] Luo C, Xu L, Zheng S, et al. Computational analysis of molecular basis of 1:1 interactions of NRG-1 wild-type and variants with ErbB3 and ErbB4. Proteins, 2005, 59(4): [12] Moreira I S, Fernandes P A, Ramos M J. Hot spot computational identification: application to the complex formed between the hen egg white lysozyme (HEL) and the antibody HyHEL-10. Int J Quantum Chem, 2007, 107(2): [13] Brady G P, Stouten P F. Fast prediction and visualization of protein binding pockets with PASS. J Comput Aided Mol Des, 2000, 14(4): [14] Kortemme T, Baker D. A simple physical model for binding energy hot spots in protein-protein complexes. Proc Natl Acad Sci USA, 2002, 99 (22): [15] Chene P. Drugs targeting protein-protein interactions. Chem Med Chem, 2006, 1(4): [16] Toogood P L. Inhibition of protein-protein association by small molecules: approaches and progress. J Med Chem, 2002, 45(8): [17] Cochran A G. Antagonists of protein-protein interactions. Chem Biol, 2000, 7(4): R85-R94 [18] Gabb H A, Jackson R M, Sternberg M J. Modelling protein docking using shape complementarity, electrostatics and biochemical information. J Mol Biol, 1997, 272(1): [19] Chen R, Li L, Weng Z P. ZDOCK: An initial-stage proteindocking algorithm. Proteins, 2003, 52(1): [20] Ritchie D W, Kemp G J. Protein docking using spherical polar fourier correlations. Proteins, 2000, 39(2): [21] Dominguez C, Boelens R, Bonvin A M. HADDOCK: A protein-protein docking approach based on biochemical or biophysical information. J Am Chem Soc, 2003, 125(7): [22] Shen J W, Zhang J, Luo X M, et al. Predicting proteinprotein interactions based only on sequences information. Proc Natl Acad Sci USA, 2007, 104(11): [23] Li H Y, Zawahir Z, Song L D, et al. Sequence-based design and discovery of peptide inhibitors of HIV-1 integrase: insight into the binding mode of the enzyme. J Med Chem, 2006, 49(15): [24] Estiarte M A, Rich D H. Burger s medicinal chemistry and drug discovery[m]. 6th ed. N Y: A JohnWiley and Sons, Inc., 2003, [25] Xu Y, Shi J, Yamamoto N, et al. A credit-card library approach for disrupting protein-protein interactions. Bioorg Med Chem, 2006, 14(8): [26] Trosset J Y, Dalvit C, Knapp S, et al. Inhibition of proteinprotein interactions: the discovery of druglike β-catenin inhibitors by combining virtual and biophysical screening. Proteins, 2006, 64(1): [27] Sun H, Nikolovska-Coleska Z, Yang C Y, et al. Structurebased design, synthesis, and evaluation of conformationally constrained mimetics of the second mitochondria-derived activator of caspase that target the X-linked inhibitor of apoptosis protein/caspase-9 interaction site. J Med Chem, 2004, 47(17): [28] Shiozaki E N, Chai J, Rigotti D J, et al. Mechanism of XIAPmediated inhibition of caspase-9. Mol Cell, 2003, 11(2): [29] Wu G, Chai J J, Suber T L, et al. Structural basis of IAP recognition by Smac/DIABLO. Nature, 2000, 408(6815): [30] Liu Z H, Sun C H, Olejniczak E T, et al. Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain. Nature, 2000, 408(6851): [31] Kipp R A, Case M A, Wist A D, et al. Molecular targeting of inhibitor of apoptosis proteins based on small molecule mimics of natural binding partners. Biochemistry, 2002, 41(23): [32] Nikolovska-Coleska Z, Wang R, Fang X, et al. Development and optimization of a binding assay for the XIAP BIR3 domain using fluorescence polarization. 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