Related Experiment Video
Updated: Jun 20, 2025
14:37
Modeling an Enzyme Active Site using Molecular Visualization Freeware
Published on: December 25, 2021
9.8K
Caught between a ROCK and a hard place: current challenges in structure-based drug design
1Medicinal Chemistry and Drug Design Technologies Department, Chiesi Farmaceutici S.p.A, Research Center, Largo Belloli 11/a, 43122 Parma, Italy.
Drug Discovery Today
|July 19, 2024
Summary
Structure-based drug design (SBDD) faces ongoing challenges despite numerous experimental structures. This review highlights common hurdles in computer-aided drug design (CADD) using Rho-associated protein kinase (ROCK) as a case study.
Area of Science:
- Medicinal Chemistry
- Computational Biology
- Drug Discovery
Background:
- Structure-based drug design (SBDD) has advanced significantly with increased availability of experimental target structures.
- Despite progress, computer-aided drug design (CADD) implementation remains complex and faces persistent challenges.
Purpose of the Study:
- To illustrate the practical challenges encountered in daily CADD workflows.
- To manage expectations regarding CADD capabilities and inform non-CADD scientists about existing difficulties.
Main Methods:
- Utilized public domain structures and data for Rho-associated protein kinase (ROCK).
- Employed a case study approach focusing on a specific drug target (ROCK) to demonstrate CADD complexities.
Main Results:
- Identified and detailed several common challenges faced by CADD scientists.
- The ROCK case study exemplifies the practical difficulties in applying CADD techniques.
Conclusions:
- CADD is not a straightforward process, even with abundant structural data.
- Understanding these challenges is crucial for realistic project planning and interdisciplinary collaboration in drug discovery.
Related Concept Videos
01:28Structure-Activity Relationships and Drug Design
697
Drug design is a dynamic field that involves discovering and developing new medications based on specific biological targets. This process heavily relies on structure-activity relationships (SAR) and quantitative structure-activity relationships (QSAR) to guide the design and optimization of efficient drugs.
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence...
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence...
697
01:26Drug Discovery: Overview
7.7K
Drug discovery is a multifaceted process involving extensive screening, testing, and optimization of lead compounds to identify potential new drugs for therapeutic use. It combines several approaches, including screening large numbers of natural products, chemical modification of known active molecules, identification of new drug targets, and rational design based on biological mechanisms and drug-receptor structure. These approaches are carried out in both academic research laboratories and...
7.7K
01:26Targets for Drug Action: Overview
6.1K
Drugs target macromolecules to modify ongoing cellular processes. Primary drug targets include receptors, ion channels, transporters, and enzymes.
Receptors are either membrane-spanning or intracellular proteins, which upon binding a ligand, get activated and transmit the signal downstream to elicit a response. Drugs bind receptors, either mimicking the action of endogenous ligands or blocking the receptor activity to bring about a modified response. Nearly 35% of approved drugs target the G...
Receptors are either membrane-spanning or intracellular proteins, which upon binding a ligand, get activated and transmit the signal downstream to elicit a response. Drugs bind receptors, either mimicking the action of endogenous ligands or blocking the receptor activity to bring about a modified response. Nearly 35% of approved drugs target the G...
6.1K
01:25Drug-Receptor Bonds
2.8K
Drug-receptor bonds are formed through various chemical forces when drugs interact with target cells. Covalent bonds, strong and irreversible, are exemplified by DNA-alkylating anticancer agents that inhibit cell division. However, such irreversible drug binding lacks selectivity and can modify the DNA of the surrounding healthy cells. Covalent binding often contributes to tissue toxicity, as seen with chloroform and paracetamol metabolites binding to the liver, causing hepatotoxicity.
In...
In...
2.8K
02:40Ligand Binding Sites
12.8K
Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
12.8K
01:20Factors Affecting Dissolution: Drug Permeability, Stability and Stereochemistry
192
Orally administered drugs primarily enter the systemic circulation via passive diffusion through the intestinal membranes. The drug's absorption is influenced by drug stability in the gastrointestinal GI tract, membrane permeability, the surface area available for absorption, luminal drug concentration, and residence time in the lumen. Drug permeability can be enhanced by adjusting the lipophilicity, polarity, or molecular size of the drug, promoting its passive transport across intestinal...
192