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Binding of small molecules at interface of protein-protein complex - A newer approach to rational drug design - PubMed

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Binding of small molecules at interface of protein-protein complex - A newer approach to rational drug design

A B Gurung et al. Saudi J Biol Sci. 2017 Feb.

Abstract

Protein-protein interaction is a vital process which drives many important physiological processes in the cell and has also been implicated in several diseases. Though the protein-protein interaction network is quite complex but understanding its interacting partners using both in silico as well as molecular biology techniques can provide better insights for targeting such interactions. Targeting protein-protein interaction with small molecules is a challenging task because of druggability issues. Nevertheless, several studies on the kinetics as well as thermodynamic properties of protein-protein interactions have immensely contributed toward better understanding of the affinity of these complexes. But, more recent studies on hot spots and interface residues have opened up new avenues in the drug discovery process. This approach has been used in the design of hot spot based modulators targeting protein-protein interaction with the objective of normalizing such interactions.

Keywords: Allosteric inhibitor; Druggability; Hot spots; Interfacial binding inhibitor; Orthosteric inhibitor; Protein interfaces.

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Figures

Figure 1
Figure 1

(A) The electrostatic potential surface of the protein complex formed between human growth hormone and growth hormone receptor [PDB ID:

1A22

]. (B) Close up view of the two hot spot residues of the growth hormone receptor TRP 104 and TRP 169 depicted in ball and stick models (green) UCSF Chimera v 1.6.1 software was used to produce this picture.

Figure 2
Figure 2

The two hybrid system: the interaction between proteins X and Y bring the DNA binding domain (DBD) and Transcriptional Activation domain (TAD) in close proximity to each other and results in reporter gene expression.

Figure 3
Figure 3

(A–D) Sequential steps involved in co-immunoprecipitation for the detection of protein–protein complexes in a protein mixture.

Figure 4
Figure 4

Three different classes of PPI modulators: (A) binding pose and molecular interaction of orthosteric inhibitor MI-2-2 bound to Menin [Protein Data Bank (PDB) code: 4GQ4]. (B) Binding pose and molecular interaction of allosteric Inhibitor PLX4032 bound to BRaf [PDB code:

3OMV

]. (C) Binding pose and molecular interaction of interfacial binding inhibitor BFA bound to ARF1–Sec7 domain complex [PDB code:

1R8Q

] the binding site of the ligand is indicated by orange rectangular box. The pictures were taken using PYMOL software v1.1.

Figure 5
Figure 5

Structures of hot spot-based design of spirooxindole core containing MDM2/p53 PPI inhibitors (A) MI-63 (B) MI-888.

Figure 6
Figure 6

Structure of hot spot-based design of hydroxyproline-containing VHL/HIF1a PPI inhibitor.

Figure 7
Figure 7

Structure of hot spot-based design of b-catenin/T-cell factor PPI inhibitor.

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