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Description

GUT-DOCK is a web service for docking of drug-like small molecules to G protein-coupled receptors. GUT-DOCK incorporates Autodock VINA and OpenBabel for ligand preparation and docking. Most of receptors included in GUT-DOCK belong to gut hormone receptors and other class B receptors which are known to be expressed in the gastrointestinal tract. Namely, GUT-DOCK performs docking of the User's compound to GCGR, GLP-1R, GIPR1, VIPR1 and PAC-1R receptors. All receptors were included in their inactive conformations. For more information on gut hormone receptors which are involved in the glucose and insulin homeostasis regulation please visit, for example, the Glucagon website. The current version of Help is a beta version which will be updated once the manuscript will be formally accepted.

Query form

User name Maximum numbers of characters: 100
E-mail address Please, enter a valid E-mail address. A link referring to results will be sent via E-mail. Otherwise, the results webpage can be saved as a bookmark.
Job description Maximum numbers of characters: 1000
Ligand binding site It is required to select either orthosteric or allosteric binding site for docking. To date, in all available crystal structures of class B GPCRs, small molecule ligands (negative allosteric modulators) were reported to be bound to the allosteric site. The orthosteric binding site of class B GPCRs is usually occupied by endogenous peptides.
Ligand file Allowed file formats: pdbqt, pdbq, pdb, mol2, sdf, smi, and mol.
File type is recognized by filename extension. For more reliable results, it is advised to submit files including a 3D structure of a ligand with added hydrogen atoms and respective partial charges. Otherwise, the ligand file is automatically converted with OpenBabel and partial atomic charges are added automatically with AutodockTools. There are rare cases when OpenBabel fails to convert a ligand file into the PDBQT file format. In such cases we advice to convert the failed ligand file into any other format using a standalone program such as, e.g., Maestro, Pymol, VMD.
Maximum allowed file size: 10 MB.

In principle, it is also possible to dock peptides with Autodock VINA. Yet, due to a significant conformational variability of peptides it is advice to dock only short peptides or only their fragments. Before docking a peptide in GUT-DOCK User should slightly edit its pdb file like in an example below. In the below example we used a small 5 amino acids-long fragment of glucagon derived from a pdb file of GCGR (PDB id: 5YQZ). Main format differences are as follows: HETATM fields instead of original ATOM fields, LIG fields instead of 3-letter codes of amino acids, 1-letter symbols of atoms instead of detailed information (e.g. CA, CB, etc.). Notably, an input conformation of a peptide can be changed because GUT-DOCK imploys a flexible-ligand docking procedure.

An original pdb file of a peptide:

ATOM      1  N   SER     2     -17.641  25.582   9.047  1.00 94.83           N  
ATOM      2  CA  SER     2     -17.865  25.510  10.486  1.00 93.56           C  
ATOM      3  C   SER     2     -17.799  24.078  11.002  1.00 95.71           C  
ATOM      4  O   SER     2     -17.815  23.886  12.218  1.00 96.23           O  
ATOM      5  CB  SER     2     -19.208  26.132  10.846  1.00 96.76           C  
ATOM      6  OG  SER     2     -19.215  27.517  10.548  1.00106.48           O  
ATOM      7  N   GLN     3     -17.707  23.075  10.085  1.00 89.57           N  
ATOM      8  CA  GLN     3     -17.629  21.639  10.403  1.00 87.68           C  
ATOM      9  C   GLN     3     -16.570  21.327  11.458  1.00 88.82           C  
ATOM     10  O   GLN     3     -16.912  20.821  12.532  1.00 87.72           O  
ATOM     11  CB  GLN     3     -17.436  20.791   9.131  1.00 88.54           C  
ATOM     12  CG  GLN     3     -17.470  19.280   9.374  1.00 93.86           C  
ATOM     13  CD  GLN     3     -18.696  18.834  10.133  1.00107.29           C  
ATOM     14  NE2 GLN     3     -18.506  18.391  11.359  1.00 95.43           N  
ATOM     15  OE1 GLN     3     -19.820  18.881   9.633  1.00104.16           O  
ATOM     16  N   GLY     4     -15.320  21.682  11.156  1.00 83.96           N  
ATOM     17  CA  GLY     4     -14.196  21.534  12.068  1.00 83.79           C  
ATOM     18  C   GLY     4     -14.415  22.178  13.425  1.00 87.90           C  
ATOM     19  O   GLY     4     -14.060  21.589  14.448  1.00 87.98           O  
ATOM     20  N   THR     5     -15.025  23.383  13.458  1.00 85.05           N  
ATOM     21  CA  THR     5     -15.353  24.170  14.662  1.00 83.71           C  
ATOM     22  C   THR     5     -16.486  23.482  15.477  1.00 89.82           C  
ATOM     23  O   THR     5     -16.498  23.568  16.707  1.00 89.79           O  
ATOM     24  CB  THR     5     -15.687  25.616  14.264  1.00 87.75           C  
ATOM     25  CG2 THR     5     -15.640  26.577  15.435  1.00 80.09           C  
ATOM     26  OG1 THR     5     -14.788  26.052  13.243  1.00 94.07           O  
ATOM     27  N   PHE     6     -17.449  22.824  14.791  1.00 85.58           N  
ATOM     28  CA  PHE     6     -18.536  22.114  15.464  1.00 83.64           C  
ATOM     29  C   PHE     6     -17.921  20.849  16.062  1.00 85.41           C  
ATOM     30  O   PHE     6     -17.890  20.730  17.290  1.00 84.57           O  
ATOM     31  CB  PHE     6     -19.657  21.799  14.474  1.00 84.49           C  
ATOM     32  CG  PHE     6     -20.897  21.132  15.008  1.00 84.59           C  
ATOM     33  CD1 PHE     6     -22.044  21.868  15.266  1.00 86.87           C  
ATOM     34  CD2 PHE     6     -20.946  19.753  15.178  1.00 85.68           C  
ATOM     35  CE1 PHE     6     -23.206  21.242  15.745  1.00 88.26           C  
ATOM     36  CE2 PHE     6     -22.108  19.125  15.640  1.00 89.34           C  
ATOM     37  CZ  PHE     6     -23.231  19.873  15.922  1.00 87.87           C  
		

An edited pdb file of a peptide that fits GUT-DOCK requirements:

HETATM    1  N   LIG     1     -17.641  25.582   9.047  1.00 94.83           N  
HETATM    2  C   LIG     1     -17.865  25.510  10.486  1.00 93.56           C  
HETATM    3  C   LIG     1     -17.799  24.078  11.002  1.00 95.71           C  
HETATM    4  O   LIG     1     -17.815  23.886  12.218  1.00 96.23           O  
HETATM    5  C   LIG     1     -19.208  26.132  10.846  1.00 96.76           C  
HETATM    6  O   LIG     1     -19.215  27.517  10.548  1.00106.48           O  
HETATM    7  N   LIG     1     -17.707  23.075  10.085  1.00 89.57           N  
HETATM    8  C   LIG     1     -17.629  21.639  10.403  1.00 87.68           C  
HETATM    9  C   LIG     1     -16.570  21.327  11.458  1.00 88.82           C  
HETATM   10  O   LIG     1     -16.912  20.821  12.532  1.00 87.72           O  
HETATM   11  C   LIG     1     -17.436  20.791   9.131  1.00 88.54           C  
HETATM   12  C   LIG     1     -17.470  19.280   9.374  1.00 93.86           C  
HETATM   13  C   LIG     1     -18.696  18.834  10.133  1.00107.29           C  
HETATM   14  N   LIG     1     -18.506  18.391  11.359  1.00 95.43           N  
HETATM   15  O   LIG     1     -19.820  18.881   9.633  1.00104.16           O  
HETATM   16  N   LIG     1     -15.320  21.682  11.156  1.00 83.96           N  
HETATM   17  C   LIG     1     -14.196  21.534  12.068  1.00 83.79           C  
HETATM   18  C   LIG     1     -14.415  22.178  13.425  1.00 87.90           C  
HETATM   19  O   LIG     1     -14.060  21.589  14.448  1.00 87.98           O  
HETATM   20  N   LIG     1     -15.025  23.383  13.458  1.00 85.05           N  
HETATM   21  C   LIG     1     -15.353  24.170  14.662  1.00 83.71           C  
HETATM   22  C   LIG     1     -16.486  23.482  15.477  1.00 89.82           C  
HETATM   23  O   LIG     1     -16.498  23.568  16.707  1.00 89.79           O  
HETATM   24  C   LIG     1     -15.687  25.616  14.264  1.00 87.75           C  
HETATM   25  C   LIG     1     -15.640  26.577  15.435  1.00 80.09           C  
HETATM   26  O   LIG     1     -14.788  26.052  13.243  1.00 94.07           O  
HETATM   27  N   LIG     1     -17.449  22.824  14.791  1.00 85.58           N  
HETATM   28  C   LIG     1     -18.536  22.114  15.464  1.00 83.64           C  
HETATM   29  C   LIG     1     -17.921  20.849  16.062  1.00 85.41           C  
HETATM   30  O   LIG     1     -17.890  20.730  17.290  1.00 84.57           O  
HETATM   31  C   LIG     1     -19.657  21.799  14.474  1.00 84.49           C  
HETATM   32  C   LIG     1     -20.897  21.132  15.008  1.00 84.59           C  
HETATM   33  C   LIG     1     -22.044  21.868  15.266  1.00 86.87           C  
HETATM   34  C   LIG     1     -20.946  19.753  15.178  1.00 85.68           C  
HETATM   35  C   LIG     1     -23.206  21.242  15.745  1.00 88.26           C  
HETATM   36  C   LIG     1     -22.108  19.125  15.640  1.00 89.34           C  
HETATM   37  C   LIG     1     -23.231  19.873  15.922  1.00 87.87           C  
		

Results

GUT-DOCK provides User's ligand binding mode as a result. 3D coordinates of ligand-receptor complexes can be downloaded as PDB files. Ligand interactions are visualized with Ligplot. Additionaly, theoretical ligand binding affinity approximated by Autodock VINA scoring function is provided. More details on GUT-DOCK results are provided in the respective manuscript.

A theoretical ligand binding affinity approximated by Autodock VINA for each GPCR receptor is juxtaposed with precomputed binding affinities of known glucose homeostasis disruptors among commonly used drugs (see Table 1 and References for further details).

Table 1. Autodock VINA results for beta-blockers vs. their relative effect on glucose homeostasis.

Name		Rank based on		Combined rank					Autodock results for
		medical information	medical information & GUT-DOCK results		allosteric site of GCGR
nebivolol	1			1						-8.1
carvedilol	1			2						-7.0
labetalol	2			3						-7.2
atenolol	3			4						-5.8
metoprolol	4			5						-5.5
	    

Here, ranks refer to the probability of inducing diabetes during pharmacotherapy (e.g., a number of patients who developed new-onset diabetes during treatment). Notably, clinical data for drug-induced diabetes is often contradictory (see References).

Standard settings for Ligplot are used for visualization of polar contacts and hydrogen bonds. By comparing values of binding affinities approximated by docking scores it is possible to predict the best protein target for a User's compound among the selected GPCRs. Accuracy of such approach is limited by performance of virtual screening in drug discovery.

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