CovDock

The Advantages of Covalent Docking

With the recent resurgence in covalent drug research, computational insight into covalent docking is becoming key to understanding how covalent inhibitors can be used to address selectivity and potency challenges.

Covalent inhibitors derive their activity not only from the formation of a covalent bond between the target and the ligand but also from stabilizing non-covalent forces in the binding pocket. CovDock selects the top covalent complexes using the extensively validated Prime energy model, and calculates an apparent affinity score that captures these essential elements of a successful covalent docking process:

1. The pre-reactive ligand form occupies the binding pocket with enough residency time to facilitate the reaction of the ligand warhead with the reactive protein residue; and
2. unfavorable steric clashes and poor electrostatic contacts are prevented as the reaction proceeds.

CovDock begins with Glide docking to a receptor with the reactive residue trimmed to alanine. The receptor reactive residue is then added and sampled to form a covalent bond with the ligand in different poses. Covalent complexes are minimized using the Prime VSGB2.0 energy model to score the top covalent complexes. An apparent affinity score, based on the Glide score of pre-reactive and post-reactive poses, is also calculated to estimate binding energies for use in virtual screening.

Features

Accurate binding mode prediction:
CovDock is built upon a foundation of the time-tested Glide docking algorithm and Prime structure refinement methodology for accurate prediction of non-covalently docked poses. Glide quickly samples a large pool of initial poses for the pre-reactive species and Prime simultaneously optimizes the ligand pose and attachment residue to produce a sound physical chemistry. The resultant accuracy outperforms other docking programs in achieving lower RMS deviations from native co-crystallized structures.

Complete workflow:
CovDock performs a series of automated steps based on a simple setup from the Maestro graphical interface or from the command line. First, CovDock docks the pre-reactive ligand to determine viable poses that bring the reactive group into close proximity with the reactive receptor residue. Then the covalent bond is formed for the top scoring complex structures, the covalently attached ligand is sampled, and the complexes are scored using all-atom molecular mechanics with the OPLS force field and VSGB2.0 implicit solvent model.

Intuitive graphical interface:
Schrödinger’s intuitive graphical user interface, Maestro, provides easy-to-use panels for straightforward set-up of experiments, easy visualization, and efficient analysis of CovDock results.

Covalent Reactions Repository

Schrödinger has made available several custom reactions that can be used in CovDock studies. To import any of the following files into Maestro, simply open the Covalent Docking Panel, click on the Reaction Type tab, select Custom from the drop-down menu, and then use the Browse option to load the reaction of interest. For more information on designing custom covalent docking reactions, please see Knowledge Base Article 1848.

 

Custom Covalent Reactions
IndexReactionLigand SMARTSReceptor SMARTSCDOCK File
1[C,c]=[C,c]-[C,c]#[N,n][C]-[S,O;H1,-1]Download
2[C;H1]([Cl])-[C](=[O])[S]-[C;H2]Download
3[C,c]#[C,c]-[C,c,S,s]=[O][C]-[S,O;H1,-1]Download
4[N]=[O,S][C,c]-[S,O;H1,-1]Download
5[N]=[C]=[S][#6]-[S;H1]Download
6[C.c]=[O,S][C,c]-[S,O;H1,-1]Download
7[C]=[C]-[C]=[O][C](=[O])-[C]-[C]Download
8[C][S][S][H][C]-[S;H1,-1]Download
9[C]=[C][c][n][C]-[S]Download
10CC[N+]([H])[H][O-]CC=ODownload
11[C]-[N]OCC(=O)Download
12[C]=[O][#6]-[O;H1]Download
13[C]=[C]-[S](=O)(=O)[C]-[N]([H])([H])([H])Download
    Download All

 

The following reaction types come pre-installed with CovDock and are shown here for reference.

Pre-Defined Reactions
ReactionLigand SMARTSReceptor ResidueCDOCK File
Beta Lactam Addition[O-0X1]=[C]1[C][C][N]1Cys, SerDownload
Boronic Acid Addition[B]([O])[O]Cys, SerDownload
Conjugate Addition to Alkyne (aryl activated)[C]#[C]-[c]Cys, SerDownload
Conjugate Addition to Alkyne (carbonyl activated)[C-0X2]#[C-0X2][C-0X3]=[O-0X1]Cys, SerDownload
Conjugate Addition to Alkene (nitrile activated)[C,c]=[C,c]-[C,c]#[N,n]Cys, SerDownload
Disulfide Formation[S;X2;H1] Download
Epoxide Opening[C;r3][O;r3][C;r3]Cys, Ser, HisDownload
Imine Condensation[C](=[O])-[C]LysDownload
Ion Pair to Covalent Bond Lig Minus1,[-1] Download
Ion Pair to Covalent Bond Lig Plus1,[+1] Download
Michael Addition[C,c]=[C,c]-[C,c,S,s]=[O]Cys, SerDownload
Nucleophilic Addition to a Double Bond[C,c]=[O,S]Cys, SerDownload
Nucleophilic Addition to a Triple Bond[C]#[N]Cys, Ser, LysDownload
Nucleophilic Substitution[F,Cl,Br,I]Cys, Ser, LysDownload
Phosphonate Addition[P]-[O;H1,-1]Cys, SerDownload
   Download All

ö "A Structure-Based Virtual Screening Approach for Discovery of Covalently Bound Ligands"

Toledo Warshaviak, D.; Golan, G.; Borrelli, K.W.; Zhu, K.; Kalid, O., J. Chem. Inf. Model, 2014, 54(7), 1941–1950

ö "Docking covalent inhibitors: A parameter free approach to pose prediction and scoring"

Zhu, K.; Borrelli, K.W.; Greenwood, J.R.; Day, T.; Abel, R.; Farid, R.S.; Harder, E., J. Chem. Inf. Model., 2014, 54, 1932−1940

Citations

Zhu, K.; Borrelli, K.W.; Greenwood, J.R.; Day, T.; Abel, R.; Farid, R.S.; Harder, E., "Docking covalent inhibitors: A parameter free approach to pose prediction and scoring," J. Chem. Inf. Model., 2014, 54, 1932−1940 

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