ArticleJournal of chemical information and modeling2020
Is Structure-Based Drug Design Ready for Selectivity Optimization?
Article in Journal of chemical information and modeling, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
17 citing papers in PubMed, 43 citations in OpenAlex.
- Next-generation Janus kinase inhibitors: Integrating synthetic innovation, structural biology, and computational design for precision drug discovery.Pharmaceutical science advances · 2026Review
- Free Energy Perturbation Simulations Measure the Change in Binding Affinity of the Aβ25-35 Peptide to the Zwitterionic Bilayer Caused by Oxidation.Journal of chemical information and modeling · 2025Article
- Multiple Molecule λ-Dynamics: Probing Drug Resistance with Concurrent Protein and Ligand Perturbations.The journal of physical chemistry letters · 2025Article
- Applying Absolute Free Energy Perturbation Molecular Dynamics to Diffusively Binding Ligands.Journal of chemical theory and computation · 2025Article
- Identification of Microbial-Based Natural Products as Potential CYP51 Inhibitors for Eumycetoma Treatment: Insights from Molecular Docking, MM-GBSA Calculations, ADMET Analysis, and Molecular Dynamics Simulations.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Fine-tuning molecular mechanics force fields to experimental free energy measurements.bioRxiv : the preprint server for biology · 2025Article
- Binding Selectivity Analysis from Alchemical Receptor Hopping and Swapping Free Energy Calculations.The journal of physical chemistry. B · 2024Article
- Molecular Dynamics Simulation Study of the Selective Inhibition of Coagulation Factor IXa over Factor Xa.Molecules (Basel, Switzerland) · 2023Article
- Assessing the performance of docking, FEP, and MM/GBSA methods on a series of KLK6 inhibitors.Journal of computer-aided molecular design · 2023Article
- Can Free Energy Perturbation Simulations Coupled with Replica-Exchange Molecular Dynamics Study Ligands with Distributed Binding Sites?Journal of chemical information and modeling · 2023Article
- Imidazole-4-N-acetamide Derivatives as a Novel Scaffold for Selective Targeting of Cyclin Dependent Kinases.Cancers · 2023Article
- Free Energy Calculations Using the Movable Type Method with Molecular Dynamics Driven Protein-Ligand Sampling.Journal of chemical information and modeling · 2022Article
- Absolute binding free energy calculations improve enrichment of actives in virtual compound screening.Scientific reports · 2022Article
- TYROSINE KINASES: COMPLEX MOLECULAR SYSTEMS CHALLENGING COMPUTATIONAL METHODOLOGIES.The European physical journal. B · 2021Article
- Potency- and Selectivity-Enhancing Mutations of Conotoxins for Nicotinic Acetylcholine Receptors Can Be Predicted Using Accurate Free-Energy Calculations.Marine drugs · 2021Article
- Cell Surface GRP94 as a Novel Emerging Therapeutic Target for Monoclonal Antibody Cancer Therapy.Cells · 2021Review
- Best Practices for Alchemical Free Energy Calculations [Article v1.0].Living journal of computational molecular science · 2020Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
Alchemical free-energy calculations are now widely used to drive or maintain potency in small-molecule lead optimization with a roughly 1 kcal/mol accuracy. Despite this, the potential to use free-energy calculations to drive optimization of compound selectivity among two similar targets has been relatively unexplored in published studies. In the most optimistic scenario, the similarity of binding sites might lead to a fortuitous cancellation of errors and allow selectivity to be predicted more accurately than affinity. Here, we assess the accuracy with which selectivity can be predicted in the context of small-molecule kinase inhibitors, considering the very similar binding sites of human kinases CDK2 and CDK9 as well as another series of ligands attempting to achieve selectivity between the more distantly related kinases CDK2 and ERK2. Using a Bayesian analysis approach, we separate systematic from statistical errors and quantify the correlation in systematic errors between selectivity targets. We find that, in the CDK2/CDK9 case, a high correlation in systematic errors suggests that free-energy calculations can have significant impact in aiding chemists in achieving selectivity, while in more distantly related kinases (CDK2/ERK2), the correlation in systematic error suggests that fortuitous cancellation may even occur between systems that are not as closely related. In both cases, the correlation in systematic error suggests that longer simulations are beneficial to properly balance statistical error with systematic error to take full advantage of the increase in apparent free-energy calculation accuracy in selectivity prediction.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.