ArticleCurrent pharmaceutical design2012
The different ways through which specificity works in orthosteric and allosteric drugs.
Article in Current pharmaceutical design, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers.
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Who cites it
67 citing papers in PubMed.
- Recent advances towards BACE1 drug discovery and therapeutics design.RSC medicinal chemistry · 2026Review
- Non-orthosteric inhibition of enolase 1 impedes growth of triple-negative breast cancer.Cell reports. Medicine · 2025Article
- Novel in silico Evidence of Bisphenol A as a Neuroinflammatory Modulator through the cGAS-STING-NLRP3 Pathway.Neurotoxicity research · 2025Article
- MDPath: Unraveling Allosteric Communication Paths of Drug Targets through Molecular Dynamics Simulations.Journal of chemical information and modeling · 2025Article
- Allostery in Disease: Anticancer Drugs, Pockets, and the Tumor Heterogeneity Challenge.Journal of molecular biology · 2025Review
- How residence time works in allosteric drugs.Current opinion in structural biology · 2025Review
- Discovery of an autoinhibited conformation in mesotrypsin reveals a strategy for selective serine protease inhibition.Science advances · 2025Article
- STINGAllo: a web server for high-throughput prediction of allosteric site-forming residues using internal protein nanoenvironment descriptors.Briefings in bioinformatics · 2025Article
- DeepAllo: allosteric site prediction using protein language model (pLM) with multitask learning.Bioinformatics (Oxford, England) · 2025Article
- Pioneer in Molecular Biology: Conformational Ensembles in Molecular Recognition, Allostery, and Cell Function.Journal of molecular biology · 2025Review
- AlloBench: A Data Set Pipeline for the Development and Benchmarking of Allosteric Site Prediction Tools.ACS omega · 2025Article
- The Missing Enzymes: A Call to Update Pharmacological Profiling Practices for Better Drug Safety Assessment.Journal of medicinal chemistry · 2025Review
- Isolation of Allosteric Tryptase Inhibitor from Methanol Extract of Rhubarb and Enhancement of Its Tryptase Inhibitory Activity by Compounds That Were Screened by In Silico Screening.Molecules (Basel, Switzerland) · 2025Article
- Medicinal Cannabis and the Intestinal Microbiome.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Global hinge sites of proteins as target sites for drug binding.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Toward the Design of Allosteric Effectors: Gaining Comprehensive Control of Drug Properties and Actions.Journal of medicinal chemistry · 2024Article
- The value of protein allostery in rational anticancer drug design: an update.Expert opinion on drug discovery · 2024Review
- Orthoflaviviral Inhibitors in Clinical Trials, Preclinical In Vivo Efficacy Targeting NS2B-NS3 and Cellular Antiviral Activity via Competitive Protease Inhibition.Molecules (Basel, Switzerland) · 2024Review
- Dissecting Allosteric Mutations for Antibiotic Resistance by Time-Dependent Linear Response Theory.Journal of chemical theory and computation · 2024Article
- Navigating the complexity of p53-DNA binding: implications for cancer therapy.Biophysical reviews · 2024Review
7 more citing papers are in PubMed but not listed here.
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Authors and funding
2 authors.
Funding
Abstract
Currently, there are two types of drugs on the market: orthosteric, which bind at the active site; and allosteric, which bind elsewhere on the protein surface, and allosterically change the conformation of the protein binding site. In this perspective we argue that the different mechanisms through which the two drug types affect protein activity and their potential pitfalls call for different considerations in drug design. The key problem facing orthosteric drugs is side effects which can occur by drug binding to homologous proteins sharing a similar binding site. Hence, orthosteric drugs should have very high affinity to the target; this would allow a low dosage to selectively achieve the goal of target-only binding. By contrast, allosteric drugs work by shifting the free energy landscape. Their binding to the protein surface perturbs the protein surface atoms, and the perturbation propagates like waves, finally reaching the binding site. Effective drugs should have atoms in good contact with the 'right' protein atoms; that is, the contacts should elicit propagation waves optimally reaching the protein binding site target. While affinity is important, the design should consider the protein conformational ensemble and the preferred propagation states. We provide examples from functional in vivo scenarios for both types of cases, and suggest how high potency can be achieved in allosteric drug development.
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