CIFDock: A novel CHARMM‐based flexible receptor–flexible ligand docking protocol

Abstract

Docking studies play a critical role in the current workflow of drug discovery. However, limitations may often arise through factors including inadequate ligand sampling, a lack of protein flexibility, scoring function inadequacies (e.g., due to metals, co‐factors, etc.), and difficulty in retaining explicit water molecules. Herein, we present a novel CHARMM‐based induced fit docking (CIFDock) workflow that can circumvent these limitations by employing all‐atom force fields coupled to enhanced sampling molecular dynamics procedures. Self‐guided Langevin dynamics simulations are used to effectively sample relevant ligand conformations, side chain orientations, crystal water positions, and active site residue motion. Protein flexibility is further enhanced by dynamic sampling of side chain orientations using an expandable rotamer library. Steps in the procedure consisting of fixing individual components (e.g., the ligand) while sampling the other components (e.g., the residues in the active site of the protein) allow for the complex to adapt to conformational changes. Ultimately, all components of the complex—the protein, ligand, and waters—are sampled simultaneously and unrestrained with SGLD to capture any induced fit effects. This modular flexible docking procedure is automated using CHARMM scripting, interfaced with SLURM array processing, and parallelized to use the desired number of processors. We validated the CIFDock procedure by performing cross‐docking studies using a data set comprised of 21 pharmaceutically relevant proteins. Five variants of the CHARMM‐based SWISSDOCK scoring functions were created to quantify the results of the final generated poses. Results obtained were comparable to, or in some cases improved upon, commercial docking program data.

Tuaimenal A, a Meroterpene from the Irish Deep-Sea Soft Coral Duva florida, Displays Inhibition of the SARS-CoV-2 3CLpro Enzyme

“…Flexible Docking of Tuaimenal A (1) in SARS-CoV-2 Protein Targets. A novel CHARMM-based flexible docking protocol, CIFDock, 29 was employed to dock 1 into the same four protein targets (3CLpro, PLpro, RdRp, and human TMPRSS2). This method allows full flexibility of the target receptor and ligand, providing a more thorough conformational space search of tuaimenal A in the active sites of these targets.…”

“…Flexible Docking. The CHARMM-based flexible docking method (CIFDock) 29 was used to flexibly dock (flexible ligand/flexible receptor) tuaimenal A (1) into all protein targets (e.g., 3CLpro, PLpro, TMPRSS2, and RdRp). CIFDock incorporates induced fit, in which ligand and protein conformational degrees of freedom can affect one another during the initial approach and complexation.…”

Identification of Potential SARS-CoV-2 Inhibitors Using Flexible Docking Based Drug Repurposing of Antivirals

“…The flexible docking portion of this study employs a novel CHARMM-based flexible docking method (CIFDock). [46] CIFDock incorporates induced fit, in which conformational changes of the ligand induce conformational changes in the protein. This method allows for enhanced flexibility of the protein-ligand complex active site, as well as retaining explicit solvent and any co-factors throughout the docking procedure.…”

CHARMM-GUI-Based Induced Fit Docking Workflow to Generate Reliable Protein–Ligand Binding Modes

“…A few computational approaches have been carefully devised to tackle this induced fit docking (IFD) problem, including Schrodinger IFD-MD, CIFDock, Fleksy, and tinyIFD. − Recently, the Schrodinger group introduced their IFD-MD (molecular dynamics) method that successfully predicted protein–ligand binding modes in 85% of 258 pairs of cross-docking cases . IFD-MD elaborately combines trained ligand-based pharmacophore docking, rigid receptor docking, energy-guided protein structure modeling, and MD simulations.…”

“…CIFDock is a CHARMM-based IFD workflow that employs self-guided Langevin dynamics simulations to sample relevant ligand conformations, side chain orientations, and water movements. Steps in their procedure include fixing individual components, i.e., the ligand, while sampling active site residues movements to account for induced fit conformational changes . Fleksy used a simpler approach of the IFD by sampling accessible side chain orientations for the selected flexible active site residues using a backbone-dependent rotamer library.…”