دورية أكاديمية
Improvements in Precision of Relative Binding Free Energy Calculations Afforded by the Alchemical Enhanced Sampling (ACES) Approach.
| العنوان: | Improvements in Precision of Relative Binding Free Energy Calculations Afforded by the Alchemical Enhanced Sampling (ACES) Approach. |
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| المؤلفون: | Tsai HC; TandemAI, New York, New York 10036, United States.; Laboratory for Biomolecular Simulation Research, Institute for Quantitative Biomedicine, and Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United States., Xu J; TandemAI, New York, New York 10036, United States., Guo Z; TandemAI, New York, New York 10036, United States., Yi Y; TandemAI, New York, New York 10036, United States., Tian C; TandemAI, New York, New York 10036, United States., Que X; TandemAI, New York, New York 10036, United States., Giese T; Laboratory for Biomolecular Simulation Research, Institute for Quantitative Biomedicine, and Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United States., Lee TS; Laboratory for Biomolecular Simulation Research, Institute for Quantitative Biomedicine, and Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United States., York DM; Laboratory for Biomolecular Simulation Research, Institute for Quantitative Biomedicine, and Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United States., Ganguly A; TandemAI, New York, New York 10036, United States., Pan A; TandemAI, New York, New York 10036, United States. |
| المصدر: | Journal of chemical information and modeling [J Chem Inf Model] 2024 Sep 23; Vol. 64 (18), pp. 7046-7055. Date of Electronic Publication: 2024 Sep 03. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 101230060 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1549-960X (Electronic) Linking ISSN: 15499596 NLM ISO Abbreviation: J Chem Inf Model Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, D.C. : American Chemical Society, c2005- |
| مواضيع طبية MeSH: | Thermodynamics* , Proteins*/chemistry , Proteins*/metabolism , Protein Binding*, Ligands ; Molecular Dynamics Simulation ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/metabolism ; Drug Discovery/methods |
| مستخلص: | Accurate in silico predictions of how strongly small molecules bind to proteins, such as those afforded by relative binding free energy (RBFE) calculations, can greatly increase the efficiency of the hit-to-lead and lead optimization stages of the drug discovery process. The success of such calculations, however, relies heavily on their precision. Here, we show that a recently developed alchemical enhanced sampling (ACES) approach can consistently improve the precision of RBFE calculations on a large and diverse set of proteins and small molecule ligands. The addition of ACES to conventional RBFE calculations lowered the average hysteresis by over 35% (0.3-0.4 kcal/mol) and the average replicate spread by over 25% (0.2-0.3 kcal/mol) across a set of 10 protein targets and 213 small molecules while maintaining similar or improved accuracy. We show in atomic detail how ACES improved convergence of several representative RBFE calculations through enhancing the sampling of important slowly transitioning ligand degrees of freedom. |
| معلومات مُعتمدة: | R01 GM107485 United States GM NIGMS NIH HHS |
| المشرفين على المادة: | 0 (Ligands) 0 (Proteins) 0 (Small Molecule Libraries) |
| تواريخ الأحداث: | Date Created: 20240903 Date Completed: 20240923 Latest Revision: 20240923 |
| رمز التحديث: | 20240923 |
| DOI: | 10.1021/acs.jcim.4c00464 |
| PMID: | 39225694 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1549-960X |
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| DOI: | 10.1021/acs.jcim.4c00464 |