Abstract
Proteins are not static objects. To carry out their functions in the cells and participate in biochemical interaction networks, proteins have to explore different conformational substates, which favor the adaptation to different partners and ultimately allow them to respond to changes in the environment. In this paper we discuss the implications of including the atomistic description of protein dynamics and flexibility in the context of drug discovery and design. The underlying idea is that a better understanding of the atomistic details of molecular recognition phenomena and conformational cross-talk between a ligand and a receptor can in fact translate in unexplored opportunities for the discovery of new drug like molecules. We will illustrate and discuss dynamics-based pharmacophores, the discovery of cryptic binding sites, the characterization and exploitation of allosteric regulation mechanisms and the definition of potential protein-protein interaction sites as potential sources of new bases for the rational design of small molecules endowed with specific biological functions. Overall, the inclusion of protein flexibility in the drug discovery process is starting to attract attention not only in the academic but also in the industrial community. This is supported by experimental tests that prove the actual feasibility of considering the explicit dynamics of drug-protein interactions at all relevant levels of resolution and the use of multiple receptor conformations in drug discovery, as affordable complements (if not an alternative) to classical High Throughput Screening (HTS) efforts based on static structures.
Keywords: Allostery, Disease, Drug design, Protein dynamics, Protein function, Protein structure.
Current Topics in Medicinal Chemistry
Title:The Dynamics of Drug Discovery
Volume: 15 Issue: 20
Author(s): Elisabetta Moroni, Antonella Paladino and Giorgio Colombo
Affiliation:
Keywords: Allostery, Disease, Drug design, Protein dynamics, Protein function, Protein structure.
Abstract: Proteins are not static objects. To carry out their functions in the cells and participate in biochemical interaction networks, proteins have to explore different conformational substates, which favor the adaptation to different partners and ultimately allow them to respond to changes in the environment. In this paper we discuss the implications of including the atomistic description of protein dynamics and flexibility in the context of drug discovery and design. The underlying idea is that a better understanding of the atomistic details of molecular recognition phenomena and conformational cross-talk between a ligand and a receptor can in fact translate in unexplored opportunities for the discovery of new drug like molecules. We will illustrate and discuss dynamics-based pharmacophores, the discovery of cryptic binding sites, the characterization and exploitation of allosteric regulation mechanisms and the definition of potential protein-protein interaction sites as potential sources of new bases for the rational design of small molecules endowed with specific biological functions. Overall, the inclusion of protein flexibility in the drug discovery process is starting to attract attention not only in the academic but also in the industrial community. This is supported by experimental tests that prove the actual feasibility of considering the explicit dynamics of drug-protein interactions at all relevant levels of resolution and the use of multiple receptor conformations in drug discovery, as affordable complements (if not an alternative) to classical High Throughput Screening (HTS) efforts based on static structures.
Export Options
About this article
Cite this article as:
Moroni Elisabetta, Paladino Antonella and Colombo Giorgio, The Dynamics of Drug Discovery, Current Topics in Medicinal Chemistry 2015; 15 (20) . https://dx.doi.org/10.2174/1568026615666150519102950
DOI https://dx.doi.org/10.2174/1568026615666150519102950 |
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
-
Chronic Pancreatitis and the Development of Pancreatic Cancer
Endocrine, Metabolic & Immune Disorders - Drug Targets Anti-Cancer Agent-Induced Nephrotoxicity
Anti-Cancer Agents in Medicinal Chemistry Hypopituitarism in Neurocritical Patients: A Case Report
Endocrine, Metabolic & Immune Disorders - Drug Targets Risk Factors for Ischemic Heart Disease
Reviews on Recent Clinical Trials An Osteoblastic Inflammatory Redox Model, using TNF-a, Glucose and Glucose- Oxidized Low- Density Lipoprotein: Targets for Minocycline
Clinical Immunology, Endocrine & Metabolic Drugs (Discontinued) Independent Relationship of Osteocalcin Circulating Levels with Obesity, Type 2 Diabetes, Hypertension, and HDL Cholesterol
Endocrine, Metabolic & Immune Disorders - Drug Targets Teratological Consequences of Nitric Oxide Synthesis Inhibition
Current Pharmaceutical Design Novel Drug Delivery System for Cancer Management: A Review
Current Cancer Therapy Reviews Preeclampsia: A Couples Disease with Maternal and Fetal Manifestations
Current Pharmaceutical Design Intestinal Uptake of Insulin Nanoparticles: Facts or Myths?
Current Pharmaceutical Biotechnology The Mediterranean and other Dietary Patterns in Secondary Cardiovascular Disease Prevention: A Review
Current Vascular Pharmacology Adipose Tissue as a Target of HIV-1 Antiretroviral Drugs. Potential Consequences on Metabolic Regulations
Current Pharmaceutical Design Crosstalk between Gut Microbiota and Central Nervous System: A Focus on Alzheimer's Disease
Current Alzheimer Research Mechanisms of Medial Arterial Calcification in Diabetes
Current Pharmaceutical Design The Honolulu-Asia Aging Study: Epidemiologic and Neuropathologic Research on Cognitive Impairment
Current Alzheimer Research Formulation and Characterization of Gliclazide Oral Dissolving Films
Drug Delivery Letters Transplantation of Genetically Modified Haematopoietic Stem Cells to Induce Antigen-Specific Tolerance as a Cure for Autoimmune Diseases
Current Stem Cell Research & Therapy Editorial [Hot Topic: Plasminogen Activator Inhibitor-1 (Guest Editor: Daniel A. Lawrence)]
Current Drug Targets Editorial [Hot Topic:The Metabolic Treatment of Coronary Artery Disease and Heart Failure(Executive Editor: Pericle Di Napoli)]
Current Pharmaceutical Design Potential Impact of Genetic Variants in Nrf2 Regulated Antioxidant Genes and Risk Prediction of Diabetes and Associated Cardiac Complications
Current Medicinal Chemistry