ArticleJournal of computer-aided molecular design2018
CDOCKER and λ-dynamics for prospective prediction in D₃R Grand Challenge 2.
Article in Journal of computer-aided molecular design, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Template-Based Docking Using Automated Maximum Common Substructure Identification with EnzyDock: Mechanistic and Inhibitor Docking.Journal of chemical information and modeling · 2025Article
- Chemically induced partial unfolding of the multifunctional apurinic/apyrimidinic endonuclease 1.Protein science : a publication of the Protein Society · 2025Review
- CHARMM-GUIJournal of chemical theory and computation · 2025Article
- Multiple Topology Replica Exchange of Expanded Ensembles for Multidimensional Alchemical Calculations.Journal of chemical theory and computation · 2025Article
- In-silico evaluation of diffractaic acid as novel anti-diabetic inhibitor against dipeptidyl peptidase IV enzyme.In silico pharmacology · 2025Article
- How to Sample Dozens of Substitutions per Site with λ Dynamics.Journal of chemical theory and computation · 2024Article
- Mechanistic docking in terpene synthases using EnzyDock.Methods in enzymology · 2024Review
- Synthesis, molecular docking, and binding Gibbs free energy calculation of β-nitrostyrene derivatives: Potential inhibitors of SARS-CoV-2 3CL protease.Journal of molecular structure · 2023Article
- A strategy for proline and glycine mutations to proteins with alchemical free energy calculations.Journal of computational chemistry · 2021Article
- D3R grand challenge 4: blind prediction of protein-ligand poses, affinity rankings, and relative binding free energies.Journal of computer-aided molecular design · 2020Article
- Improving small molecule virtual screening strategies for the next generation of therapeutics.Current opinion in chemical biology · 2018Review
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5 authors.
Funding
Abstract
The opportunity to prospectively predict ligand bound poses and free energies of binding to the Farnesoid X Receptor in the D3R Grand Challenge 2 provided a useful exercise to evaluate CHARMM based docking (CDOCKER) and [Formula: see text]-dynamics methodologies for use in "real-world" applications in computer aided drug design. In addition to measuring their current performance, several recent methodological developments have been analyzed retrospectively to highlight best procedural practices in future applications. For pose prediction with CDOCKER, when the protein structure used for rigid receptor docking was close to the crystallographic holo structure, reliable poses were obtained. Benzimidazoles, with a known holo receptor structure, were successfully docked with an average RMSD of 0.97 [Formula: see text]. Other non-benzimidazole ligands displayed less accuracy largely because the receptor structures we chose for docking were too different from the experimental holo structures. However, retrospective analysis has shown that when these ligands were re-docked into their holo structures, the average RMSD dropped to 1.18 [Formula: see text] for all ligands. When sulfonamides and spiros were docked with the apo structure, which agrees more with their holo structure than the structures we chose, five out of six ligands were correctly docked. These docking results emphasize the need for flexible receptor docking approaches. For [Formula: see text]-dynamics techniques, including multisite [Formula: see text]-dynamics (MS[Formula: see text]D), reasonable agreement with experiment was observed for the 33 ligands investigated; root mean square errors of 2.08 and 1.67 kcal/mol were obtained for free energy sets 1 and 2, respectively. Retrospectively, soft-core potentials, adaptive landscape flattening, and biasing potential replica exchange (BP-REX) algorithms were critical to model large substituent perturbations with sufficient precision and within restrictive timeframes, such as was required with participation in Grand Challenge 2. These developments, their associated benefits, and proposed procedures for their use in future applications are discussed.
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