ArticleThe journal of physical chemistry. B2015
Distinguishing binders from false positives by free energy calculations: fragment screening against the flap site of HIV protease.
Article in The journal of physical chemistry. B, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 82 citations in OpenAlex.
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- PDBrestore: A Free Web Interface for Processing and Fixing Protein Chains From Raw PDB Files.Journal of computational chemistry · 2025Article
- Exploring the Inhibitory Potential of Phytosterols β-Sitosterol, Stigmasterol, and Campesterol on 5-Alpha Reductase Activity in the Human Prostate: An In Vitro and In Silico Approach.Plants (Basel, Switzerland) · 2024Article
- The Open Force Field Initiative: Open Software and Open Science for Molecular Modeling.The journal of physical chemistry. B · 2024Article
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- Dealing with Induced Fit, Conformational Selection, and Secondary Poses in Molecular Dynamics Simulations for Reliable Free Energy Predictions.Journal of chemical theory and computation · 2023Article
- Elucidating the molecular determinants for binding modes of a third-generation HIV-1 integrase strand transfer inhibitor: Importance of side chain and solvent reorganization.bioRxiv : the preprint server for biology · 2023Article
- Past, Present, and Future Perspectives on Computer-Aided Drug Design Methodologies.Molecules (Basel, Switzerland) · 2023Review
- Identification of CYP3A4 inhibitors as potential anti-cancer agents using pharmacoinformatics approach.Journal of molecular modeling · 2023Article
- Identification of novel inhibitors for SARS-CoV-2 as therapeutic options using machine learning-based virtual screening, molecular docking and MD simulation.Frontiers in molecular biosciences · 2023Article
- Virtual screening of Indonesian herbal compounds as COVID-19 supportive therapy: machine learning and pharmacophore modeling approaches.BMC complementary medicine and therapies · 2022Article
- Structure-based virtual screening workflow to identify antivirals targeting HIV-1 capsid.Journal of computer-aided molecular design · 2022Article
- Essential Dynamics Ensemble Docking for Structure-Based GPCR Drug Discovery.Frontiers in molecular biosciences · 2022Article
- Multiple Poses and Thermodynamics of Ligands Targeting Protein Surfaces: The Case of Furosemide Binding to mitoNEET in Aqueous Solution.Frontiers in cell and developmental biology · 2022Article
- Accommodating receptor flexibility and free energy calculation to reduce false positive binders in the discovery of natural products blockers of SARS-COV-2 spike RBD-ACE2 interface.Biochemistry and biophysics reports · 2021Article
- Computational Studies of Selected Transition Metal Complexes as Potential Drug Candidates against the SARS-CoV-2 Virus.ChemistrySelect · 2021Article
- Evaluation of log P, pKJournal of computer-aided molecular design · 2021Article
- Exploring naltrexamine derivatives featuring azaindole moiety via nitrogen-walk approach to investigate their in vitro pharmacological profiles at the mu opioid receptor.Bioorganic & medicinal chemistry letters · 2021Article
- Article
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
Abstract
Molecular docking is a powerful tool used in drug discovery and structural biology for predicting the structures of ligand-receptor complexes. However, the accuracy of docking calculations can be limited by factors such as the neglect of protein reorganization in the scoring function; as a result, ligand screening can produce a high rate of false positive hits. Although absolute binding free energy methods still have difficulty in accurately rank-ordering binders, we believe that they can be fruitfully employed to distinguish binders from nonbinders and reduce the false positive rate. Here we study a set of ligands that dock favorably to a newly discovered, potentially allosteric site on the flap of HIV-1 protease. Fragment binding to this site stabilizes a closed form of protease, which could be exploited for the design of allosteric inhibitors. Twenty-three top-ranked protein-ligand complexes from AutoDock were subject to the free energy screening using two methods, the recently developed binding energy analysis method (BEDAM) and the standard double decoupling method (DDM). Free energy calculations correctly identified most of the false positives (≥83%) and recovered all the confirmed binders. The results show a gap averaging ≥3.7 kcal/mol, separating the binders and the false positives. We present a formula that decomposes the binding free energy into contributions from the receptor conformational macrostates, which provides insights into the roles of different binding modes. Our binding free energy component analysis further suggests that improving the treatment for the desolvation penalty associated with the unfulfilled polar groups could reduce the rate of false positive hits in docking. The current study demonstrates that the combination of docking with free energy methods can be very useful for more accurate ligand screening against valuable drug targets.
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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.