Surfing the Protein-Protein Interaction Surface Using Docking Methods: Application to the Design of PPI Inhibitors

Sable, Rushikesh; Jois, Seetharama D.

doi:10.3390/molecules200611569

Cited by 75 publications

(45 citation statements)

References 241 publications

(189 reference statements)

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“…The 2B5 Fab has about 575 Å 2 surface area buried, 405 Å 2 on the heavy chain and 170 Å 2 on the light chain, involving more than 9 and 6 residues, respectively. Although in both cases the Fab-Fab interface is significantly smaller than most other protein-protein interaction (PPI) areas that range from 1200 Å 2 to 2000 Å 2 , it is comparable to those in the active-site-like PPI for transient docking [24,25]. Presumably the Fab dimers of 3.3 and 2B5 do not form spontaneously in the absence of PEG.…”

Section: Formation Of Fab Dimer By Peg Bindingmentioning

confidence: 85%

Structural basis of polyethylene glycol recognition by antibody

Lee

et al. 2020

J Biomed Sci

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Background: Polyethylene glycol (PEG) is widely used in industry and medicine. Anti-PEG antibodies have been developed for characterizing PEGylated drugs and other applications. However, the underlying mechanism for specific PEG binding has not been elucidated. Methods: The Fab of two cognate anti-PEG antibodies 3.3 and 2B5 were each crystallized in complex with PEG, and their structures were determined by X-ray diffraction. The PEG-Fab interactions in these two crystals were analyzed and compared with those in a PEG-containing crystal of an unrelated anti-hemagglutinin 32D6-Fab. The PEG-binding stoichiometry was examined by using analytical ultracentrifuge (AUC).Results: A common PEG-binding mode to 3.3 and 2B5 is seen with an S-shaped core PEG fragment bound to two dyad-related Fab molecules. A nearby satellite binding site may accommodate parts of a longer PEG molecule. The core PEG fragment mainly interacts with the heavy-chain residues D31, W33, L102, Y103 and Y104, making extensive contacts with the aromatic side chains. At the center of each half-circle of the S-shaped PEG, a water molecule makes alternating hydrogen bonds to the ether oxygen atoms, in a similar configuration to that of a crown ether-bound lysine. Each satellite fragment is clamped between two arginine residues, R52 from the heavy chain and R29 from the light chain, and also interacts with several aromatic side chains. In contrast, the nonspecifically bound PEG fragments in the 32D6-Fab crystal are located in the elbow region or at lattice contacts. The AUC data suggest that 3.3-Fab exists as a monomer in PEG-free solution but forms a dimer in the presence of PEG-550-MME, which is about the size of the S-shaped core PEG fragment. Conclusions:The differing amino acids in 3.3 and 2B5 are not involved in PEG binding but engaged in dimer formation. In particular, the light-chain residue K53 of 2B5-Fab makes significant contacts with the other Fab in a dimer, whereas the corresponding N53 of 3.3-Fab does not. This difference in the protein-protein interaction between two Fab molecules in a dimer may explain the temperature dependence of 2B5 in PEG binding, as well as its inhibition by crown ether.

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Section: Formation Of Fab Dimer By Peg Bindingmentioning

confidence: 85%

Structural basis of polyethylene glycol recognition by antibody

Lee

et al. 2020

J Biomed Sci

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“…Analysis of protein-protein complex 3D structures shows that contact surfaces of PPIs range from 1,000–4,000 Å 2 [26], and the average area of the interfaces is 1,600 Å 2 [27], which is much larger than traditional ligand binding pockets, which vary from 300 to 1,000 Å 2 [26]. From a geometrical point of view, most PPI interfaces have planar shapes [28–30], except for intertwined interface structures [31], and they do not have a groove where a small molecule binds to.…”

Section: Characteristics Of Ppis and Smppiismentioning

confidence: 99%

In silico structure-based approaches to discover protein-protein interaction-targeting drugs

Shin

Christoffer

Kihara

2017

Methods

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A core concept behind modern drug discovery is finding a small molecule that modulates a function of a target protein. This concept has been successfully applied since the mid-1970s. However, the efficiency of drug discovery is decreasing because the druggable target space in the human proteome is limited. Recently, protein-protein interaction (PPI) has been identified as an emerging target space for drug discovery. PPI plays a pivotal role in biological pathways including diseases. Current human interactome research suggests that the number of PPIs ranges from 130,000 to 650,000, and only a small number of them have been targeted as drug targets. For traditional drug targets, in silico structure-based methods have been successful in many cases. However, their performance suffers on PPI interfaces because PPI interfaces are different in five major aspects: From a geometric standpoint, they have relatively large interface regions, flat geometry, and the interface surface shape tends to fluctuate upon binding. Also, their interactions are dominated by hydrophobic atoms, which is different from traditional binding-pocket-targeted drugs. Finally, PPI targets usually lack natural molecules that bind to the target PPI interface. Here, we first summarize characteristics of PPI interfaces and their known binders. Then, we will review existing in silico structure-based approaches for discovering small molecules that bind to PPI interfaces.

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“…Sable, and S. Jois, [14] evaluated a docking methodology in PPI design. For therapeutic purposes, only a few methods were succeeding in the combination of both experimental and docking methods with scoring function.…”

Section: Literature Reviewmentioning

confidence: 99%

Identification of Lung Cancer Related Genes Using Enhanced Floyd Warshall Algorithm in a Protein to Protein Interaction Network

Patil¹,

Patil²,

Manickam³

2018

IJIES

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Lung cancer is defined as an uncontrolled cell growing in the tissues of lung, which is also said to be lung tumor. The lung cancer is curable in the starting stage, but identifying the lung cancer in starting stage is very difficult. In recent decades, researchers showed great interest on gene level lung cancer identification using shortest path between the lung cancer related genes. Many research has been done to identify the shortest path between the genes, but the conventional methods consumes more time for processing the data. In this research, Protein to Protein Interaction (PPI) structure is constructed from the weighted protein present in the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. For identifying the shortest path between the genes in PPI, an effective algorithm: enhanced Floyd warshall algorithm is proposed. Floyd warshall is efficient in finding the shortest path between the genes and also solves all pairs of shortest path problem. A major drawback of Floyd warshall algorithm is, it works slower than other conventional algorithms designed to perform the same task. To improve the performance of traditional Floyd warshall algorithm, an iterative matrix is used for eliminating the invalid path. Then, the comparison between the proposed method and existing system is given in the experimental result. Experimental outcome shows that the proposed approach improved the time consumption up to 2-3 sec compared to the existing methods: Dijkstra's algorithm and Floyd warshall algorithm.Keywords: Dijkstra's algorithm, Enhanced Floyd warshall algorithm, Protein to protein interaction, Search tool for the retrieval of interacting genes/proteins.

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Surfing the Protein-Protein Interaction Surface Using Docking Methods: Application to the Design of PPI Inhibitors

Cited by 75 publications

References 241 publications

Structural basis of polyethylene glycol recognition by antibody

Structural basis of polyethylene glycol recognition by antibody

In silico structure-based approaches to discover protein-protein interaction-targeting drugs

Identification of Lung Cancer Related Genes Using Enhanced Floyd Warshall Algorithm in a Protein to Protein Interaction Network

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