Computationally designed prodrugs of statins based on Kirby's enzyme model
Rafik Karaman1, Wajd Amly, Laura Scrano
1Bioorganic Chemistry Department, Faculty of Pharmacy, Al-Quds University, P. O. Box 20002, Jerusalem, Palestine. dr_karaman@yahoo.com
Journal of Molecular Modeling
|July 10, 2013
Summary
Density Functional Theory (DFT) calculations reveal that intramolecular proton transfer rates in enzyme models depend linearly on distance and angle. This informs the design of simvastatin prodrugs for enhanced bioavailability and controlled drug release.
Area of Science:
- Computational Chemistry
- Enzyme Kinetics
- Medicinal Chemistry
Background:
- Intramolecular proton transfer is crucial in enzymatic reactions.
- Understanding reaction rate determinants is key for drug design.
- Simvastatin bioavailability can be improved through prodrug strategies.
Purpose of the Study:
- To investigate the factors influencing intramolecular proton transfer rates in enzyme models.
- To design novel simvastatin prodrugs with potentially enhanced bioavailability.
- To establish a correlation between prodrug structure and drug release rate.
Main Methods:
- Density Functional Theory (DFT) calculations at the B3LYP/6-31G(d,p) level.
- Analysis of reaction rate dependence on geometric parameters (rGM, α).
- Design and in silico evaluation of three simvastatin prodrugs.
Main Results:
- Reaction rate of intramolecular proton transfer is linearly correlated with the distance between reacting centers (rGM) and hydrogen bonding angle (α).
- Three simvastatin prodrugs were designed based on DFT findings.
- Simvastatin prodrug ProD 3 is predicted to release simvastatin approximately 10 times faster than ProD 1 or ProD 2.
Conclusions:
- Geometric parameters significantly influence intramolecular proton transfer rates in enzyme models.
- The design of prodrugs can be guided by computational modeling for controlled drug release.
- Structural features of the promoiety dictate the rate of simvastatin release from its prodrugs.
More Related Videos
10:29Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
14:34A Bilingual Computational Workflow for Identifying Potential PLK1 Inhibitors in American Sign Language and English
Published on: April 3, 2026
Related Concept Videos
01:30Prodrugs
Prodrugs are a class of pharmaceutical compounds that undergo a biotransformation process within the body to be converted into a pharmacologically active drug. Prodrugs are designed to improve the therapeutic properties of the parent drug, such as enhancing bioavailability, increasing stability, or reducing toxicity. The concept of prodrugs revolves around modifying the chemical structure of the original drug to make it more effective or convenient for administration.
Prodrugs help overcome...
Prodrugs help overcome...
01:20Lipid-Lowering Drugs: Statins and Miscellaneous Agents
Hyperlipidemia, a medical condition often referred to as high cholesterol, is characterized by abnormally elevated levels of lipids in the bloodstream. When present in excess, these lipids, specifically cholesterol and triglycerides, can lead to serious health complications, often involving cardiovascular diseases. Illnesses like atherosclerosis, heart attacks, and pancreatitis have all been linked to untreated hyperlipidemia. This means controlling and regulating cholesterol and triglyceride...
01:16Protein-Drug Binding: Mechanism and Kinetics
Protein-drug binding refers to the interaction between drugs and proteins within the body. This binding process can occur intracellularly, involving drug interactions with enzymes or receptors within cells, or extracellularly, involving plasma proteins in the blood.
Various forces drive these interactions, including hydrogen bonds, hydrophobic interactions, ionic bonds, electrostatic interactions, and van der Waals forces. These bonds enable drugs to bind to specific sites on proteins,...
Various forces drive these interactions, including hydrogen bonds, hydrophobic interactions, ionic bonds, electrostatic interactions, and van der Waals forces. These bonds enable drugs to bind to specific sites on proteins,...
01:07Physiological Pharmacokinetic Models: Incorporating Hepatic Transporter-Mediated Clearance
Drug transporters are critical in drug absorption, distribution, and excretion processes. They should be included in physiological-based pharmacokinetic (PBPK) models, which help predict human drug disposition. However, predicting this is challenging during drug development, especially when liver transport is involved. However, with a realistic representation of body transport processes, an accurate model may be possible.
A recent model describes pravastatin's hepatobiliary excretion, mediated...
A recent model describes pravastatin's hepatobiliary excretion, mediated...
01:28Structure-Activity Relationships and Drug Design
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 its...
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 its...
01:24Pharmacokinetic–Pharmacodynamic Relationship: Problems
The empirical approach to drug therapy optimization relies on correlating pharmacological response with administered dosage. Such an approach can be costly, time-consuming, and often yields poor correlation due to variables like formulation factors and drug elimination characteristics. A more precise approach correlates response with plasma drug concentration or the amount of drug in the body, rather than dosage. This is achieved through pharmacokinetic-pharmacodynamic (PK/PD) modeling, which...