Research progress in protein-protein interactions and their inhibitors

19 5 2007 10 Chinese Bulletin of Life Sciences Vol. 19, No. 5 Oct., 2007 1004-0374(2007)05-0506-06 ( 200237) - - - - - - - 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 200237, 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) 2007-04-28 2007-06-15 (20572023) (1982 ) ytang234@ecust.edu.cn (1968 ) * E-mail

5 507 1 1999 2006 FDA NMEs(http://www. fda.gov/cder/rdmt/default.htm) - [2] - - p53-hdm2 [3] - [4-5] 1 - ( ph ) - 1.1 Jones Thornton [6] 59 368Å 2 4 746Å 2 639Å 2 3 228Å 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] - - 1.2 [6] 1.3 -

508 19 [6] - 56% 29% 15% [15] 1.4 π-π π K D 10-9 10-12 mol/l K D 10-6 10-9 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] 2 - - 3D-Dock [18] ZDOCK [19] Hex [20] HADDOCK [21] - - [22] - 80% - 3 - - -

5 509-3.1 ( ) [23] 3.2 (structure-based drug design SBDD) - 1997 (human immunodeficiency virus HIV) [24] 3.3 - 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]

510 19 Smac XIAP caspase-9 4.1 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-9 5-4 AVPI 1

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