Flexible CDOCKER: Development and application of a pseudo‐explicit structure‐based docking method within CHARMM

Abstract

Protein-ligand docking is a commonly used method for lead identification and refinement. While traditional structure-based docking methods represent the receptor as a rigid body, recent developments have been moving toward the inclusion of protein flexibility. Proteins exist in an inter-converting ensemble of conformational states, but effectively and efficiently searching the conformational space available to both the receptor and ligand remains a well-appreciated computational challenge. To this end, we have developed the Flexible CDOCKER method as an extension of the family of complete docking solutions available within CHARMM. This method integrates atomically detailed side chain flexibility with grid-based docking methods, maintaining efficiency while allowing the protein and ligand configurations to explore their conformational space simultaneously. This is in contrast to existing approaches that use induced-fit like sampling, such as Glide or Autodock, where the protein or the ligand space is sampled independently in an iterative fashion. Presented here are developments to the CHARMM docking methodology to incorporate receptor flexibility and improvements to the sampling protocol as demonstrated with re-docking trials on a subset of the CCDC/Astex set. These developments within CDOCKER achieve docking accuracy competitive with or exceeding the performance of other widely utilized docking programs.

Comparison of 6‐mercaptopurine with 6‐thioguanine for the analysis of thiopurine S‐methyltransferase activity in human erythrocyte by LC–MS/MS

“…To determine whether 6‐MP and 6‐TG had similar affinities for the active center of TPMT, the interaction of 6‐MP and 6‐TG with the active center of TPMT was evaluated via a computer‐based simulation using Discovery Studio software (BIOVIA, version 4.5). CDOCKER was used for molecular docking and CDOCKER Energy was used to represent the affinity (Gagnon, Law, & Brooks, ). The crystal structure of murine TPMT as a ternary complex with S‐ adenosyl‐ l ‐homocysteine and 6‐MP (PDB ID: 3BGD) was used (Peng et al, ).…”

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“…The pose cluster radius was set to 0.5Å and ten random conformations were generated from equilibration and minimization of the ligand structure. CDocker uses the CHARMM forcefield and combining the molecular dynamics with docking provides better accuracy than other methods [28][29][30]. The active site in the groove region of the β-catenin where TCF4 binds was chosen for the study and is shown in Fig.2.…”

Combined comparative molecular field analysis, comparative molecular similarity indices analysis, molecular docking and molecular dynamics studies of histone deacetylase 6 inhibitors

“…Next, compounds were allowed to dock into the catalytic site of the receptor. Docking was performed using CDOCKER (Gagnon, Law, & Brooks, ) (uses grid‐based MD docking algorithm) of Discovery Studio 4.0 and docking scores such as CDOCKER Energy, CDOCKER Interaction Energy (Gagnon et al., ), Ligscore1, Ligscore2 (Krammer, Kirchhoff, Jiang, Venkatachalam, & Waldman, ), PLP1 (Gehlhaar et al., ), PLP2 (Verkhivker et al., ), PMF (Muegge & Martin, ), Ludi1, Ludi2 and Ludi3 (Böhm, ) were computed. Docking scores of all compounds have been enumerated in Supporting Information Table S3.…”