ArticleJournal of computer-aided molecular design2019
Complex macrocycle exploration: parallel, heuristic, and constraint-based conformer generation using ForceGen.
Article in Journal of computer-aided molecular design, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Dynamics of (Hetero)aryl Motifs: An Integrative Approach To Study the Conformational Landscape in Macrocycles.Journal of the American Chemical Society · 2026Article
- Rapid Generation of Transition-State Conformer Ensembles via Constrained Distance Geometry.Journal of chemical information and modeling · 2026Article
- Exploring Macrocyclic Chemical Space: Strategies and Technologies for Drug Discovery.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Structure-based pose prediction: Non-cognate docking extended to macrocyclic ligands.Journal of computer-aided molecular design · 2024Article
- From UK-2A to florylpicoxamid: Active learning to identify a mimic of a macrocyclic natural product.Journal of computer-aided molecular design · 2024Article
- Complex peptide macrocycle optimization: combining NMR restraints with conformational analysis to guide structure-based and ligand-based design.Journal of computer-aided molecular design · 2023Article
- High-Quality Conformer Generation with CONFORGE: Algorithm and Performance Assessment.Journal of chemical information and modeling · 2023Article
- Unmasking the True Identity of Rapamycin's Minor Conformer.Journal of natural products · 2023Article
- Cell-permeable chameleonic peptides: Exploiting conformational dynamics in de novo cyclic peptide design.Current opinion in structural biology · 2023Review
- A Distributional Model of Bound Ligand Conformational Strain: From Small Molecules up to Large Peptidic Macrocycles.Journal of medicinal chemistry · 2023Article
- Discovery and Biosynthesis of a Structurally Dynamic Antibacterial Diterpenoid.Angewandte Chemie (International ed. in English) · 2021Article
- Geometrically Diverse Lariat Peptide Scaffolds Reveal an Untapped Chemical Space of High Membrane Permeability.Journal of the American Chemical Society · 2021Article
- Cheminformatics in Natural Product-based Drug Discovery.Molecular informatics · 2020Review
- The role of NMR in leveraging dynamics and entropy in drug design.Journal of biomolecular NMR · 2020Article
- Structure-based drug repositioning over the human TMPRSS2 protease domain: search for chemical probes able to repress SARS-CoV-2 Spike protein cleavages.European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences · 2020Article
- Macrocycle Cell Permeability Measured by Solvation Free Energies in Polar and Apolar Environments.Journal of chemical information and modeling · 2020Article
- Coupling enhanced sampling of the apo-receptor with template-based ligand conformers selection: performance in pose prediction in the D3R Grand Challenge 4.Journal of computer-aided molecular design · 2020Article
- Electrostatic-field and surface-shape similarity for virtual screening and pose prediction.Journal of computer-aided molecular design · 2019Article
- Heterophyllin B: Combining Isotropic and Anisotropic NMR for the Conformational Analysis of a Natural Occurring Cyclic Peptide.Magnetic resonance in chemistry : MRCArticle
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7 authors.
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Abstract
ForceGen is a template-free, non-stochastic approach for 2D to 3D structure generation and conformational elaboration for small molecules, including both non-macrocycles and macrocycles. For conformational search of non-macrocycles, ForceGen is both faster and more accurate than the best of all tested methods on a very large, independently curated benchmark of 2859 PDB ligands. In this study, the primary results are on macrocycles, including results for 431 unique examples from four separate benchmarks. These include complex peptide and peptide-like cases that can form networks of internal hydrogen bonds. By making use of new physical movements ("flips" of near-linear sub-cycles and explicit formation of hydrogen bonds), ForceGen exhibited statistically significantly better performance for overall RMS deviation from experimental coordinates than all other approaches. The algorithmic approach offers natural parallelization across multiple computing-cores. On a modest multi-core workstation, for all but the most complex macrocycles, median wall-clock times were generally under a minute in fast search mode and under 2 min using thorough search. On the most complex cases (roughly cyclic decapeptides and larger) explicit exploration of likely hydrogen bonding networks yielded marked improvements, but with calculation times increasing to several minutes and in some cases to roughly an hour for fast search. In complex cases, utilization of NMR data to constrain conformational search produces accurate conformational ensembles representative of solution state macrocycle behavior. On macrocycles of typical complexity (up to 21 rotatable macrocyclic and exocyclic bonds), design-focused macrocycle optimization can be practically supported by computational chemistry at interactive time-scales, with conformational ensemble accuracy equaling what is seen with non-macrocyclic ligands. For more complex macrocycles, inclusion of sparse biophysical data is a helpful adjunct to computation.
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