Abstract
Whereas docking screens have emerged as the most practical way to use protein structure for ligand discovery, an inconsistent track record raises questions about how well docking actually works. In its favor, a growing number of publications report the successful discovery of new ligands, often supported by experimental affinity data and controls for artifacts. Few reports, however, actually test the underlying structural hypotheses that docking makes. To be successful and not just lucky, prospective docking must not only rank a true ligand among the top scoring compounds, it must also correctly orient the ligand so the score it receives is biophysically sound. If the correct binding pose is not predicted, a skeptic might well infer that the discovery was serendipitous. Surveying over 15 years of the docking literature, we were surprised to discover how rarely sufficient evidence is presented to establish whether docking actually worked for the right reasons. The paucity of experimental tests of theoretically predicted poses undermines confidence in a technique that has otherwise become widely accepted. Of course, solving a crystal structure is not always possible, and even when it is, it can be a lot of work, and is not readily accessible to all groups. Even when a structure can be determined, investigators may prefer to gloss over an erroneous structural prediction to better focus on their discovery. Still, the absence of a direct test of theory by experiment is a loss for method developers seeking to understand and improve docking methods. We hope this review will motivate investigators to solve structures and compare them with their predictions whenever possible, to advance the field.
Keywords: Virtual screening, ligand discovery
Current Topics in Medicinal Chemistry
Title: Docking Screens: Right for the Right Reasons?
Volume: 9 Issue: 9
Author(s): Peter Kolb and John J. Irwin
Affiliation:
Keywords: Virtual screening, ligand discovery
Abstract: Whereas docking screens have emerged as the most practical way to use protein structure for ligand discovery, an inconsistent track record raises questions about how well docking actually works. In its favor, a growing number of publications report the successful discovery of new ligands, often supported by experimental affinity data and controls for artifacts. Few reports, however, actually test the underlying structural hypotheses that docking makes. To be successful and not just lucky, prospective docking must not only rank a true ligand among the top scoring compounds, it must also correctly orient the ligand so the score it receives is biophysically sound. If the correct binding pose is not predicted, a skeptic might well infer that the discovery was serendipitous. Surveying over 15 years of the docking literature, we were surprised to discover how rarely sufficient evidence is presented to establish whether docking actually worked for the right reasons. The paucity of experimental tests of theoretically predicted poses undermines confidence in a technique that has otherwise become widely accepted. Of course, solving a crystal structure is not always possible, and even when it is, it can be a lot of work, and is not readily accessible to all groups. Even when a structure can be determined, investigators may prefer to gloss over an erroneous structural prediction to better focus on their discovery. Still, the absence of a direct test of theory by experiment is a loss for method developers seeking to understand and improve docking methods. We hope this review will motivate investigators to solve structures and compare them with their predictions whenever possible, to advance the field.
Export Options
About this article
Cite this article as:
Kolb Peter and Irwin J. John, Docking Screens: Right for the Right Reasons?, Current Topics in Medicinal Chemistry 2009; 9 (9) . https://dx.doi.org/10.2174/156802609789207091
DOI https://dx.doi.org/10.2174/156802609789207091 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
The Potential of Microalgae for the Production of Bioactive Molecules of Pharmaceutical Interest
Current Pharmaceutical Biotechnology A Systems Medicine Clinical Platform for Understanding and Managing Non- Communicable Diseases
Current Pharmaceutical Design Suramin Attenuated Inflammation and Reversed Skin Tissue Damage in Experimentally Induced Atopic Dermatitis in Mice
Inflammation & Allergy - Drug Targets (Discontinued) Osteoarthritis: Is there a Window of Opportunity
Current Rheumatology Reviews Vascular Factors and Mitochondrial Dysfunction: a Central Role in the Pathogenesis of Alzheimer’s Disease
Current Neurovascular Research Neurodegeneration with Dementia: From Fundamentals of Pathology to Clinical Imaging by MRI and SPECT.
Current Medical Imaging Morphological and Functional Features of the Sex Steroid-Responsive Posterodorsal Medial Amygdala of Adult Rats
Mini-Reviews in Medicinal Chemistry The Significant Role of Nutraceutical Compounds in Ulcerative Colitis Treatment
Current Medicinal Chemistry Chalcone Derivatives Activate and Desensitize the Transient Receptor Potential Ankyrin 1 Cation Channel, Subfamily A, Member 1 TRPA1 Ion Channel: Structure-Activity Relationships in vitro and Anti-Nociceptive and Anti-inflammatory Activity in vivo
CNS & Neurological Disorders - Drug Targets Effects of GHB On Psychomotor and Driving Performance
Current Drug Metabolism Preface
Current Drug Targets - CNS & Neurological Disorders Traffic in the Operating Room: A Review of Factors Influencing Air Flow and Surgical Wound Contamination.
Infectious Disorders - Drug Targets Dysfunction of Magnocellular/dorsal Processing Stream in Schizophrenia
Current Psychiatry Research and Reviews Psychiatric Disorders and TRP Channels: Focus on Psychotropic Drugs
Current Neuropharmacology Unsuspected Intrinsic Property of Melanin to Dissociate Water Can Be Used for the Treatment of CNS Diseases
CNS & Neurological Disorders - Drug Targets Neural Induction and Patterning in Mammalian Pluripotent Stem Cells
CNS & Neurological Disorders - Drug Targets Small Interfering RNAs and Antisense Oligonucleotides for Treatment of Neurological Diseases
Current Drug Targets Neuroimaging Features of Acquired Metabolic and Toxic Encephalopathies
Current Medical Imaging Intestinal Barrier Dysfunction in Human Pathology and Aging
Current Pharmaceutical Design Cefepime-Induced Neurotoxicity
Central Nervous System Agents in Medicinal Chemistry