Related Experiment Video
Updated: Nov 18, 2025
Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
Published on: December 9, 2015
Molecular modeling approaches to address drug-metabolizing enzymes (DMEs) mediated chemoresistance: a review
Baddipadige Raju1, Shalki Choudhary1, Gera Narendra1
1Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India.
Abstract:
Resistance against clinically approved anticancer drugs is the main roadblock in cancer treatment. Drug metabolizing enzymes (DMEs) that are capable of metabolizing a variety of xenobiotic get overexpressed in malignant cells, therefore, catalyzing drug inactivation. As evident from the literature reports, the levels of DMEs increase in cancer cells that ultimately lead to drug inactivation followed by drug resistance. To puzzle out this issue, several strategies inclusive of analog designing, prodrug designing, and inhibitor designing have been forged. On that front, the implementation of computational tools can be considered a fascinating approach to address the problem of chemoresistance. Various research groups have adopted different molecular modeling tools for the investigation of DMEs mediated toxicity problems. However, the utilization of these in-silico tools in maneuvering the DME mediated chemoresistance is least considered and yet to be explored. These tools can be employed in the designing of such chemotherapeutic agents that are devoid of the resistance problem. The current review canvasses various molecular modeling approaches that can be implemented to address this issue. Special focus was laid on the development of specific inhibitors of DMEs. Additionally, the strategies to bypass the DMEs mediated drug metabolism were also contemplated in this report that includes analogs and pro-drugs designing. Different strategies discussed in the review will be beneficial in designing novel chemotherapeutic agents that depreciate the resistance problem.
Insights
Drug resistance in cancer is a major challenge. This review explores computational tools and strategies like inhibitor and prodrug design to overcome drug inactivation by drug metabolizing enzymes (DMEs) in cancer cells.
Area of Science:
- Computational chemistry and drug discovery
- Oncology and cancer therapeutics
Background:
- Anticancer drug resistance is a significant obstacle in cancer treatment.
- Overexpression of drug metabolizing enzymes (DMEs) in cancer cells leads to rapid drug inactivation and resistance.
- Current strategies to combat resistance include analog and prodrug design.
Purpose of the Study:
- To review the application of computational tools, specifically molecular modeling, in addressing chemoresistance.
- To highlight the potential of in-silico approaches for designing novel anticancer agents that circumvent drug resistance.
- To focus on strategies for developing specific DME inhibitors and bypassing DME-mediated drug metabolism.
Main Methods:
- Literature review of molecular modeling approaches for investigating DME-mediated toxicity and resistance.
- Analysis of strategies including analog design, prodrug design, and inhibitor design.
- Exploration of in-silico tools for predicting and mitigating drug inactivation by DMEs.
Main Results:
- Computational tools offer a promising avenue for understanding and overcoming drug resistance.
- The development of specific DME inhibitors can restore drug efficacy.
- Designing analogs and prodrugs can effectively bypass DME-mediated inactivation.
Conclusions:
- In-silico methodologies are underutilized but hold significant potential for tackling chemoresistance.
- Strategic drug design, guided by computational approaches, can lead to the development of novel chemotherapeutic agents.
- These strategies aim to create drugs that are less susceptible to inactivation by DMEs, thereby improving treatment outcomes.
More Related Videos
08:59Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down
Published on: December 11, 2017
09:58Using RNA-sequencing to Detect Novel Splice Variants Related to Drug Resistance in In Vitro Cancer Models
Published on: December 9, 2016
Related Concept Videos
02:56Treatment Resistant Cancers
01:21Factors Affecting Drug Biotransformation: Physicochemical and Chemical Properties of Drugs
The drug's acidity or basicity is essential in...
01:26Targets for Drug Action: Overview
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...
01:07Physiological Pharmacokinetic Models: Incorporating Hepatic Transporter-Mediated Clearance
A recent model describes pravastatin's hepatobiliary excretion,...
01:19Factors Affecting Drug Biotransformation: Biological
Species differences: Variations in enzyme systems across species can cause disparities in drug metabolism. For instance, humans may metabolize certain drugs faster than rodents, altering therapeutic effects.
Strain differences: Genetic variations within a species can result in differing enzyme activity, impacting drug response and toxicity. For example, some mouse strains may...
01:28Structure-Activity Relationships and Drug Design
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...