How Does Biochemistry Influence Drug Development?

Learn about the crucial role biochemistry plays in drug development in this article.

laboratory test tubes and drug

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Biochemistry provides the foundation for understanding the biochemical pathways and molecular interactions that underlie various diseases. By studying these mechanisms, biochemists can identify potential targets for therapeutic intervention and design target-specific drugs.

Introduction to Biochemistry in Drug Development

One of the primary reasons why understanding biochemical pathways and molecular interactions is essential to drug development is the need for specificity. Biochemical pathways are a series of interconnected reactions that regulate cellular processes. By identifying the specific molecules involved in these pathways, scientists can design drugs that selectively modulate their activity.

This targeted approach minimizes the risk of off-target reactions and can reduce the likelihood of adverse effects. In addition, understanding these molecular interactions is critical to ensuring safety and efficacy.

Target Identification and Validation

Before the advent of omics technologies, biochemists relied on a range of experimental techniques to identify and validate molecular targets for new drugs, such as phenotypic screening and target-based drug discovery.

Phenotypic screening involves the testing of compounds in living models to observe and measure changes in their observable characteristics. This approach seeks to identify compounds that can effectively modulate the desired phenotypic outcome without necessarily understanding the molecular mechanism involved.

In contrast, target-based drug discovery focuses on identifying compounds that interact with specific molecular targets known to be involved in a particular disease. This approach relies on a deep understanding of the underlying biological mechanisms and aims to develop compounds that selectively and efficiently modulate the activity of these targets.

One example is angiotensin-converting enzyme (ACE), an enzyme involved in blood pressure regulation. In the 1970s, through extensive screening of chemical libraries, scientists discovered a drug called captopril that could inhibit ACE activity; this drug became the first ACE inhibitor and revolutionized the treatment of hypertension.

Target identification has evolved over the past few decades with the development of omics technologies. By using techniques such as genomics, proteomics and metabolomics to identify molecules associated with a particular disease and comparing the profiles of healthy and diseased samples, it is possible to select potential targets that are overexpressed, mutated or dysregulated.

Once potential targets are identified, biochemists employ various validation techniques to confirm their significance and potential as drug targets. These validation methods include in vitro and in vivo experiments and cell-based assays to assess the functional impact of modulating the target. In vivo experiments provide further evidence of target validity by evaluating the efficacy and safety of drug candidates.

Drug Design and Molecular Modeling

Biochemical knowledge plays a critical role in the design phase of drug development, providing insights into molecular interactions and pathways that are critical for identifying and optimizing potential drug candidates. Historically, drug design has relied heavily on empirical approaches. However, with advances in computational methods, biochemists now have powerful tools to aid in the design of new drugs.

One of the most significant advances in recent years has been using computational models and simulations to predict drug-target interactions. These methods use molecular docking, molecular dynamics simulations, and quantitative structure-activity relationships (QSAR) to predict how potential drug molecules interact with their target proteins.

Molecular docking algorithms (e.g., AutoDock, GOLD and MOE) predict the binding affinities of drugs to target proteins. Molecular dynamics simulations provide insight into their stability and conformational changes, and QSAR models attempt to correlate the structural features of drug molecules with their potential biological activity.

A notable breakthrough in computational modeling is the development of AlphaFold and its derivatives (e.g., Alphafold Multimer and MULTICOM), an artificial intelligence system that predicts 3D protein structures from amino acid sequences with remarkable accuracy. This information is critical in drug design because the structure of a target protein determines how a drug molecule interacts with it.

Optimizing Drug Efficacy and Safety

Biochemistry plays a critical role in optimizing the pharmacokinetics and pharmacodynamics of drugs. In the early stages of drug development, biochemical assays are used to evaluate the pharmacokinetic properties of potential drug candidates. These assays measure parameters such as drug absorption, distribution, metabolism and excretion (ADME). This information helps optimize drug dosing regimens and predict potential drug-drug interactions.

Biochemical assays are also used to evaluate potential side effects and toxicity. These assays evaluate the effects of drugs on various cellular processes.Systems biology is one of the most recent methods to address the selection and enhancement of pharmaceuticals.

One such is the NTNU initiative DrugLogics, which aims to develop and integrate computational, experimental, and analytical methods to predict and validate anti-cancer drug combinations and create an integrated pipeline for clinical decision support through rational screening of synergistic drugs in precision medicine. It also attempts to build and apply computer models to anticipate cancer treatment resistance.

Biotechnology in Drug Development

Recombinant DNA technologies are a key biotechnological tool that has had a significant impact on the field of biologically derived drugs. It involves the manipulation and transfer of DNA between different organisms. This technique allows scientists to produce large quantities of specific proteins that may have therapeutic activity.

Monoclonal antibodies are examples of this. Although there are different methods for their production, recombinant DNA technology is one of them. These antibodies can be designed to act as therapeutic drugs targeting certain molecules in the body.

Two notable examples are Herceptin (trastuzumab), which is used to treat HER2-positive breast cancer, and tumor necrosis factor (TNF) inhibitors, such as adalimumab (Humira), that neutralize the effects of TNF, an important inflammatory cytokine involved in rheumatoid arthritis.

Conclusion

From the initial discovery of potential drug targets to optimizing drug efficacy and safety, biochemistry serves as a foundation for understanding the molecular mechanisms underlying diseases and drug activities. It contributes to target identification and validation, drug selection, design and optimization, as well as pharmacokinetics, pharmacodynamics and safety assessment.

It is important to notice that interdisciplinary collaboration is essential in advancing this field, since the complex nature of drug development requires expertise from various scientific disciplines, including biochemistry, pharmacology, computational biology, medicinal chemistry, and clinical research.

Sources:

Liu, J, et al. (2023). Enhancing Alphafold-Multimer-Based Protein Complex Structure Prediction with Multicom in CASP15. doi.org/10.1101/2023.05.16.541055

Shepard, H. M., et al. (2017). Developments in therapy with monoclonal antibodies and related proteins. Clinical Medicine, 17(3), pp. 220–232. doi.org/10.7861/clinmedicine.17-3-220

Swinney, D. C. (2013). Phenotypic vs. target-based drug discovery for first-in-class medicines. Clinical Pharmacology & Therapeutics, 93(4), pp. 299–301. doi.org/10.1038/clpt.2012.236

Yang, X., et al. (2023). OTTM: An automated classification tool for translational drug discovery from OMICS data. Briefings in Bioinformatics, 24(5). doi.org/10.1093/bib/bbad301

Bryan J. (2009) From snake venom to ACE inhibitor - the discovery and rise of Captopril. The Pharmaceutical Journal. Available at: pharmaceutical-journal.com/.../from-snake-venom-to-ace-inhibitor-the-discovery-and-rise-of-captopril

The DRUGLOGICS initiative. The Druglogics Initiative. (n.d.) [online]. Available at: https://druglogics.eu/

Plagiarism report: smallseotools.com/plagiarism-report/d5e24b2b6c71d3e72dcd702feed09f76

Further Reading

Last Updated: Dec 27, 2023

Deliana Infante

Written by

Deliana Infante

I am Deliana, a biologist from the Simón Bolívar University (Venezuela). I have been working in research laboratories since 2016. In 2019, I joined The Immunopathology Laboratory of the Venezuelan Institute for Scientific Research (IVIC) as a research-associated professional, that is, a research assistant.

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