Science Background
Paragraph description of the science/background for this CURE:
The research theme at the heart of this CURE is a perennial problem facing drug development- how can you achieve specificity for a pathogen target when host (Human) homologs exist. Malaria, caused by the pathogen Plasmodium falciparum (Pfalciparum) is an excellent example. Both pathogen and host depend on Malate Dehydrogenase as a key part of their energy metabolism. Pfalciparum Malate Dehydrogenase is tetrameric while the human homologs are dimeric- do the oligomeric differences allow specific targeting of inhibitors to preferentially inhibit the Pfalciparum enzyme. Although Malate Dehydrogenases in general show overall tertiary structure similarities there are some regions of sequence difference between Pfalciparum and Human forms of mDH that, as we have shown, may lead to the existence of unique cryptic allosteric sites that could be targeted for allosteric drug design. Similarly, subtle differences in the active site regions could be exploited for orthosteric drug design. In addition to ligand specificity, bioavailability issues involving exploring the Physicochemical Design Space of potential “lead” compounds for future drug design are also incorporated.
Relevant Literature that support this science:
“Allosterism and Drug Discovery” Bell, E & Bell J., Burger’s Medicinal Chemistry, Drug Discovery and Development, Eighth Edition. Volume 2, pages 163-240, 2021. Publisher- Wiley
The existence of a Cryptic Allosteric Site on Plasmodium falciparum Malate Dehydrogenase
Natalie Botros, Ellis Bell, Jessica Bell, First published: 18 April 2020, https://doi.org/10.1096/fasebj.2020.34.s1.05326
Potential Drug Design for Plasmodium falciparum Malate Dehydrogenase Targeting the Cryptic Allosteric Site, Natalie Botros, Ellis Bell, Jessica Bell First published: 14 May 2021, https://doi.org/10.1096/fasebj.2021.35.S1.02936
A fragment-based approach identifies an allosteric pocket that impacts malate dehydrogenase activity. Reyes Romero A, Lunev S, Popowicz GM, Calderone V, Gentili M, Sattler M, Plewka J, Taube M, Kozak M, Holak TA, Dömling ASS, Groves MR.Commun Biol. 2021 Aug 10;4(1):949. doi: 10.1038/s42003-021-02442-1.
Oligomeric interfaces as a tool in drug discovery: Specific interference with activity of malate dehydrogenase of Plasmodium falciparum in vitro
Sergey Lunev 1, Sabine Butzloff 2, Atilio R Romero 1, Marleen Linzke 3, Fernando A Batista 1, Kamila A Meissner 3, Ingrid B Müller 2, Alaa Adawy 1, Carsten Wrenger 3, Matthew R Groves 1
PLoS One, 2018 Apr 25;13(4):e0195011., doi: 10.1371/journal.pone.0195011. eCollection 2018.
Abstract 2087: Exploring the role of the dimer interface in Plasmodium falciparum malate dehydrogenase: The impact of Q11I, I15Q, L19N and L22N mutations on quaternary structure and enzymatic properties. Daniel Armendariz, Diego Hernandez, Megan Keene, Jessica Bell & Ellis Bell, Journal of Biological Chemistry (2023) Vol. 299Issue 3SupplementPublished in issue: 2023
Abstract 2111: Using enzyme kinetics and computational docking studies to understand substrate and inhibitor interactions with human mitochondrial, human cytosolic, watermelon glyoxysomal and Plasmodium falciparum malate dehydrogenases. Diego Hernandez, Jessica Bell & Ellis Bell , Journal of Biological Chemistry (2023), Volume 299, Issue 3, 103638
Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings Christopher A. Lipinski”, Franc0 I,ombardo, Beryl W. Dominy, Paul J. Feeney, Advanced Drug Delivery Reviews 23 (1997) 3-25, doi: 10.1016/s0169-409x(00)00129-0. PMID: 11259830