ArticleJournal of the American Chemical Society2011
Full protein flexibility is essential for proper hot-spot mapping.
Article in Journal of the American Chemical Society, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed, 126 citations in OpenAlex.
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- Accurate Protein Dynamic Conformational Ensembles: Combining AlphaFold, MD, and AmideInternational journal of molecular sciences · 2025Article
- Structure-Based Experimental Datasets for Benchmarking Protein Simulation Force Fields [Article v1.0].Living journal of computational molecular science · 2025Article
- Accelerating fragment-based drug discovery using grand canonical nonequilibrium candidate Monte Carlo.Nature communications · 2025Article
- Exploration of Cryptic Pockets Using Enhanced Sampling Along Normal Modes: A Case Study of KRASJournal of chemical information and modeling · 2024Article
- Enhancing SILCS-MC via GPU Acceleration and Ligand Conformational Optimization with Genetic and Parallel Tempering Algorithms.The journal of physical chemistry. B · 2024Article
- Expanding FTMap for Fragment-Based Identification of Pharmacophore Regions in Ligand Binding Sites.Journal of chemical information and modeling · 2024Article
- Classification of likely functional class for ligand binding sites identified from fragment screening.Communications biology · 2024Article
- In Silico Exploration of the Trypanothione Reductase (TryR) ofInternational journal of molecular sciences · 2023Article
- Exploiting the Innate Plasticity of the Programmed Cell Death-1 (PD1) Receptor to Design Pembrolizumab H3 Loop Mimics.Chembiochem : a European journal of chemical biology · 2022Article
- Evaluating the use of absolute binding free energy in the fragment optimisation process.Communications chemistry · 2022Article
- Cosolvent Simulations with Fragment-Bound Proteins Identify Hot Spots to Direct Lead Growth.Journal of chemical theory and computation · 2022Article
- Computational Cosolvent Mapping Analysis Leads to Identify Salicylic Acid Analogs as Weak Inhibitors of ST2 and IL33 Binding.The journal of physical chemistry. B · 2022Article
- Enhancing Sampling of Water Rehydration on Ligand Binding: A Comparison of Techniques.Journal of chemical theory and computation · 2022Article
- Application of Site-Identification by Ligand Competitive Saturation in Computer-Aided Drug Design.New journal of chemistry = Nouveau journal de chimie · 2022Article
- In Silico Analysis of Peptide Macrocycle -Protein Interactions.Methods in molecular biology (Clifton, N.J.) · 2022Article
- The druggable genome: Twenty years later.Frontiers in bioinformatics · 2022Article
- Identification of Cryptic Binding Sites Using MixMD with Standard and Accelerated Molecular Dynamics.Journal of chemical information and modeling · 2021Article
- Chemical validation of a druggable site on Hsp27/HSPB1 using in silico solvent mapping and biophysical methods.Bioorganic & medicinal chemistry · 2021Article
- Cosolvent Analysis Toolkit (CAT): a robust hotspot identification platform for cosolvent simulations of proteins to expand the druggable proteome.Scientific reports · 2019Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
A traditional technique for structure-based drug design (SBDD) is mapping of protein surfaces with probe molecules to identify "hot spots" where key functional groups can best complement the receptor. Common methods, such as minimization of probes or calculation of grids, use a fixed protein structure in the gas phase, ignoring both protein flexibility and proper competition between the probes and water. As a result, the potential surface is quite rugged, and many spurious local minima are identified. In this work, we compared rigid and fully flexible proteins in mixed-solvent molecular dynamics, which allows for flexibility and full solvent effects. We were surprised to find that the large number of local minima are still found when a protein's conformational sampling is restricted; the dynamic averaging of probes and competition with water do not smooth the potential surface as one might expect. Only when a protein is allowed to be fully flexible in the simulation are the proper minima located and the spurious ones eliminated. Our results indicate that inclusion of full protein flexibility is critical to accurate hot-spot mapping for SBDD.
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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.