Drug Design

• INTRODUCTION

  Drug design for metabolic enzymes involves the identification, characterization, screening, and optimization of potential therapeutic agents that target specific enzymes involved in metabolic pathways. Firstly, target enzymes associated with metabolic dysregulation and disease are identified based on their roles in aberrant metabolic processes. The three-dimensional structure and catalytic mechanism of the target enzyme are then characterized to facilitate rational drug design. This includes determining the enzyme's atomic-level structure and understanding the active site architecture to identify potential binding pockets. Through high-throughput screening and virtual screening techniques, small molecules or compounds are screened to identify those that interact with the target enzyme and show favorable binding interactions. Promising drug candidates undergo lead optimization, where chemical modifications are made to improve their potency, selectivity, and pharmacokinetic properties. Structure-activity relationship (SAR) studies help understand the relationship between chemical structure and biological activity. This iterative process leads to the development of optimized drug candidates that can selectively modulate the activity or function of specific metabolic enzymes, aiming to restore normal metabolic function and mitigate disease symptoms.

  Drug design approaches can be tailored to specifically target metabolic enzymes in parasites as compared to human enzymes. For example, in the case of malaria, drugs called artemisinin-based combination therapies (ACTs) have been developed to disrupt the heme metabolism of the Plasmodium parasite, causing its death. In antifungal drug design, compounds known as azoles inhibit the enzyme lanosterol 14α-demethylase, which is crucial for fungal ergosterol biosynthesis. By blocking this enzyme, azole drugs disrupt the integrity of the fungal cell membrane, leading to growth inhibition. Similarly, antiparasitic drug design focuses on targeting unique metabolic pathways in parasites. The drug pentamidine, for instance, inhibits the enzyme trypanothione reductase, disrupting redox homeostasis in trypanosomes and leishmaniasis-causing parasites. Lastly, antihelminthic drugs can selectively target metabolic enzymes or processes in parasitic worms. Praziquantel, for instance, affects schistosomes by increasing calcium ion permeability in their cell membranes, resulting in muscle paralysis and subsequent death. These targeted approaches aim to disrupt specific metabolic pathways in parasites while minimizing adverse effects on human metabolic enzymes.

  There are currently no drugs specifically designed to target MDH as a therapeutic strategy in clinical trials. However several publications show progress in this area. MDH is an essential enzyme involved in various metabolic pathways, and its dysregulation is associated with several diseases. However, the development of drugs directly targeting MDH has been challenging due to the enzyme's ubiquitous presence and the potential for adverse effects on normal cellular function. However, it's worth noting that indirect targeting of MDH-related pathways or downstream effects of MDH dysregulation may be employed in the development of therapeutic interventions. For example, in diseases where MDH plays a significant role, such as cancer, efforts may focus on targeting other enzymes or signaling pathways associated with abnormal MDH activity.

• PROJECT IDEAS

  Use computational approaches to define inhibitors at active site or in unique allosteric pockets unique between human and parasite MDH.

  Develop a colorimetric assay to test MDH in a high throughput drug screen

  Conduct a screen of potential inhibitors using a small molecule/compound library of a fragment library to screen potential inhibitors (link to database)

  The Bell lab (jbell@sandiego.edu) is actively working on several interesting ongoing projects.

  More Coming Soon - have something to contribute? email josephprovost@sandiego.edu

Information & Resources

• A mix of human and parasite MDH Clones

• Drug discovery for enzymes (Drug Discovery Today 2021)

• Mechanistic enzymology in drug discovery: A fresh perspective (Nature Reviews Drug Discovery 2017)

Relevant Publications

• A fragment-based approach identifies an allosteric pocket that impacts malate dehydrogenase activity (Commun Biology 2021)

• Lactate dehydrogenase and malate dehydrogenase: Potential antiparasitic targets for drug development studies (Bioorg Med Chem 2021)

• A Novel Malate Dehydrogenase 2 Inhibitor Suppresses Hypoxia-Inducible Factor-1 by Regulating Mitochondrial Respiration (PLoS One 2016)

• W1497, an Inhibitor of Malate Dehydrogenase, Suppresses TGF-β1-Induced Epithelial-Mesenchymal Transition in Lung Cancer Cells by Downregulating Slug (Antioxidants (Basel) 2021)

• Oligomeric interfaces as a tool in drug discovery: Specific interference with activity of malate dehydrogenase of Plasmodium falciparum in vitro (PLoS One 2018)

• Synthesis and structure-activity relationship study of chemical probes as hypoxia induced factor-1α/malate dehydrogenase 2 inhibitors (J Med Chem 2014)

List of Skills/ Techniques Needed: Computational docking of potential drug with MDH, molecular techniques, expression and purification, circular dichroism, fast thermal melt, enzyme assays.

A list of adopters:: Ellis Bell, Jessica Bell, David Hecht, (email josephprovost@sandiego.edu to add your name!)