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.

Cold water benthic environments are a prolific source of structurally diverse molecules with a range of bioactivities against human disease. Specimens of a previously chemically unexplored soft coral, Duva florida , were collected during a deep-sea cruise that sampled marine invertebrates along the Irish continental margin in 2018. Tuaimenal A ( 1 ), a cyclized merosesquiterpenoid representing a new carbon scaffold with a highly substituted chromene core, was discovered through exploration of the soft coral secondary metabolome via NMR-guided fractionation. The absolute configuration was determined through vibrational circular dichroism. Functional biochemical assays and in silico docking experiments found tuaimenal A selectively inhibits the viral main protease (3CLpro) of SARS-CoV-2.

Cold water benthic environments are a prolific source of structurally diverse molecules with a range of bioactivity against human disease. Specimens of a previously chemically unexplored soft coral, <i>Drifa</i> sp., were collected during a deep-sea cruise that sampled marine invertebrates along the Irish continental margin in 2018. Tuaimenal A (<b>1</b>), a cyclized merosesquiterpenoid representing a new carbon scaffold with a highly substituted chromene core, was discovered through exploration of the soft coral secondary metabolome via NMR-guided fractionation. Absolute stereochemistry was determined through vibrational circular dichroism. Functional assays and <i>in silico</i> docking experiments found tuaimenal A active against two major health burdens: SARS-CoV-2 and cancer. Biochemical and cell-based assays established that tuaimenal A effectively and selectively inhibits the viral main protease (3CLpro) and mitigates proliferation of cervical cancer cells lines. Given the need for novel treatment options for both diseases, our data suggest that tuaimenal A and/or its derivates could culminate in the development of a unique and effective drug.

A selection of antiviral compounds from the Drug Repurposing Hub were screened as potential inhibitors against SARS-CoV-2 protein targets using CIFDock, a flexible docking method. CIFDock allows for a fully flexible active site of the protein-ligand complex and retaining of explicit water molecules throughout docking simulations. This method provides a more thorough conformational space search than is attainable by rigid docking methods, and thus a more accurate representation of the binding interactions between these antiviral compounds and the SARS-CoV-2 protein targets. Four proteins critical to viral function were selected as targets of the study: the main protease (Mpro), the papain-like protease (PLpro), the transmembrane protease (TMPRSS2), and the RNA-dependent RNA-polymerase (RdRp). The results reveal potential SARS-CoV-2 viral inhibitors from this library of antivirals, based on favorable Glide scores of the docked protein-ligand poses. The antiviral compounds brecanavir, mozenavir, palinavir, sovaprevir, and telinavir yielded excellent binding scores across all protease targets. Additionally, these particular antivirals have not yet been investigated in clinical trials nor in vitro studies regarding COVID-19. Therefore, these compounds can be recommended for further research against SARS-CoV-2, based on extensive docking analysis with relevant protein targets.

Cold water benthic environments are a prolific source of structurally diverse molecules with a range of bioactivities against human disease. Specimens of a previously chemically unexplored soft coral, Duva florida, were collected during a deep-sea cruise that sampled marine invertebrates along the Irish continental margin in 2018. Tuaimenal A (1), a cyclized merosesquiterpenoid representing a new carbon scaffold with a highly substituted chromene core, was discovered through exploration of the soft coral secondary metabolome via NMR-guided fractionation. The absolute stereochemistry was determined through vibrational circular dichroism. Functional biochemical assays and in silico docking experiments found tuaimenal A selectively inhibits the viral main protease (3CLpro) of SARS-CoV-2.