Docking Covalent Inhibitors: A Parameter Free Approach To Pose Prediction and Scoring

Abstract

Although many popular docking programs include a facility to account for covalent ligands, large-scale systematic docking validation studies of covalent inhibitors have been sparse. In this paper, we present the development and validation of a novel approach for docking and scoring covalent inhibitors, which consists of conventional noncovalent docking, heuristic formation of the covalent attachment point, and structural refinement of the protein-ligand complex. This approach combines the strengths of the docking program Glide and the protein structure modeling program Prime and does not require any parameter fitting for the study of additional covalent reaction types. We first test this method by predicting the native binding geometry of 38 covalently bound complexes. The average RMSD of the predicted poses is 1.52 Å, and 76% of test set inhibitors have an RMSD of less than 2.0 Å. In addition, the apparent affinity score constructed herein is tested on a virtual screening study and the characterization of the SAR properties of two different series of congeneric compounds with satisfactory success.

Tricyclic Covalent Inhibitors Selectively Target Jak3 through an Active Site Thiol

“…The structure of basic tricyclic core is shown on the right. c, Compound 3 modeled into Jak3 using a covalent docking method from the program Glide using 4QPS monomer C as a reference model (41).…”

Peptide‐Directed Binding for the Discovery of Modulators of α‐Helix‐Mediated Protein–Protein Interactions: Proof‐of‐Concept Studies with the Apoptosis Regulator Mcl‐1

“…Covalent docking studies were performed on ac atalogue of azides,m odelling aHuisgen cycloaddition (see the Supporting Information for details). Ther esults were scored and ranked, [19] and those highly ranked structures that were synthetically and economically viable were chosen for synthesis.Similarly,amino acids 75-84 of the peptide were virtually removed, and azidoacetic acid was attached to the N-terminus of amino acids 85-93.…”

Pharmacological Inhibition of the Protein Kinase MRK/ZAK Radiosensitizes Medulloblastoma

“…M443 structure was constructed in 2D Sketcher and subsequently prepared by LigPrep module (version 3.4, Schr€ odinger, LLC, 2015) in Maestro. The CovDock docking program (20) within the Schr€ odinger suite was employed for M443 and MRK covalent docking. Cysteine 22 on MRK was targeted as the reactive residue to undergo Michael addition with compound M443.…”

“…Cysteine 22 on MRK was targeted as the reactive residue to undergo Michael addition with compound M443. The ranking of poses by affinity score calculates the average of the pre-reacted and post-reacted Glide score for the given pose (20). The top ranking CovDock affinity pose was chosen as the final pose of M443.…”