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Hits and Lead Discovery in the Identification of New Drugs against the Trypanosomatidic Infections
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Theodora Calogeropoulou, George E. Magoulas, Ina Pöhner, Joanna Panecka-Hofman, Pasquale Linciano, Stefania Ferrari, Nuno Santarem, Ma Dolores Jiménez-Antón, Ana Isabel Olías-Molero, José María Alunda, Anabela Cordeiro da Silva, Rebecca C. Wade, Maria Paola Costi
Targeting the kinetoplastid folate pathway, unlike the corresponding malarial (Hawser et al. 2006) and bacterial (Yuthavong et al. 2005) pathways, requires not only the inhibition of dihydrofolate reductase (DHFR), but also of pteridine reductase 1 (PTR1) (Bello et al. 1994, Sienkiewicz et al. 2010). The latter enzyme is mainly responsible for the reduction of pterins, but can be upregulated when DHFR is inhibited and serve as a bypass for folate reduction to provide necessary educts for DNA synthesis and thus ensure parasite survival (Dawson et al. 2006, Vickers and Beverley 2011). In T. brucei, PTR1 was validated as a potential drug target by gene knockout and RNA interference experiments (Ong et al. 2011, Sienkiewicz et al. 2010). Herein, we mostly focus on inhibitor design for PTR1 from T. cruzi and T. brucei. Multiple drug design approaches have been used to target PTR1, starting from optimization of the substrate scaffold, through virtual screening (VS), to fragment-based drug design (FBDD).
Anti-trypanosomatid structure-based drug design – lessons learned from targeting the folate pathway
Published in Expert Opinion on Drug Discovery, 2022
Joanna Panecka-Hofman, Ina Poehner, Rebecca C. Wade
In the folate pathway (Figure 2), folates are reduced to produce metabolites for DNA synthesis. Blocking the folate pathway is a strategy that has been pursued in anti-cancer, anti-bacterial and anti-malarial drug design [33–35]. A similar approach has been taken for anti-trypanosomatid drug design [36–38]. Whereas in the former cases, this strategy requires inhibiting dihydrofolate reductase (DHFR), for trypanosomatids, apart from DHFR (in the bifunctional DHFR-TS enzyme), pteridine reductase 1 (PTR1) also needs to be inhibited (Figure 2). PTR1 can reduce pterins and folate, and when DHFR is inhibited, it can act as a bypass enzyme and retain folate reduction [39,40]. Notably, PTR1 is not present in humans and therefore targeting PTR1 provides a way to specifically target the parasite folate pathway while minimizing side-effects. The recent applications of SBDD against the trypanosomatid folate pathway discussed here focus mostly on PTR1, with parasite DHFR (from DHFR-TS) often being treated as an additional target. Parasite TS was rarely targeted because the sequence similarity of this enzyme in trypanosomatids to the human homologue is very high, hindering the design of selective antiparasitic compounds [41].
Synthesis and biological evaluation of thiazolidinedione derivatives with high ligand efficiency to P. aeruginosa PhzS
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Thamires Quadros Froes, Bianca Trindade Chaves, Marina Sena Mendes, Rafael Matos Ximenes, Ivanildo Mangueira da Silva, Priscila Brandão Gomes da Silva, Julianna Ferreira Cavalcanti de Albuquerque, Marcelo Santos Castilho
Compounds bearing the 4-thiazolidinone, 2,4-thiazolidinedione, rhodanine (2-thioxo-4-thiazolidinone) moieties have been explored by medicinal chemists since the 1960s1,2. In fact, many authors claim that 4-thiazolidinone ring might be considered a privileged scaffold for drug design efforts3,4. One of the main achievements that have fuelled the drug design efforts with 4-thiazolidinone derivatives was the introduction of antidiabetic drugs to the market (i.e. peroxisome proliferator-activated receptor-g (PPAR) agonists5 and aldose reductase inhibitors6) However, this class of compounds has also shown promise in several fields (Figure 1). For instance, 5-arylidene-2,4-thiazolidinone derivatives are low micromolar inhibitors of Pteridine reductase 1 from Leishmania major7 that are also active against L. braziliensis and L. infantum promastigotes8, and benzylidene-2,4-thiazolidinedione derivatives9 and thiazolidine-2,4-diones derivatives with a carboxylic ester substituent at N-310 have shown activity against protein-tyrosine phosphatase 1B (PTP1B). More recently, Froes and co-workers included the inhibition of P. aeruginosa PhzS to the list of biological activities ascribed to compounds bearing the 2,4-thiazolidinedione ring and underscored that these compounds might be employed to battle resistant bacteria11.
Fragment-based screening with natural products for novel anti-parasitic disease drug discovery
Published in Expert Opinion on Drug Discovery, 2019
Fragment-based drug discovery using virtual screening targeted T. brucei pteridine reductase 1 (TbPTR1), a potential target to treat human African trypanosomiasis, enzyme [39]. A serial of physico-chemical property filters, including less than 20 heavy atoms, less than two ring systems, at least one hydrogen-bond donor, less than four rotatable bonds, and a ClogP/ClogD ratil below 3.5 was applied to a commercially available library of 250,000 compounds, resulting in 26,084 fragment-like molecules. The fragment library was docked into the TbPTR1 binding site and ranked based on docking scores. Subsequent filters, such as dissimilarity with known inhibitors and PSA less than 70 A, were used to generate 59 compounds for experiment test. Three fragments (46–48) (Figure 12) showed more than 50% inhibition of TbPTR1 at concentration of 100 μM and two were available for further analog development. The most potent phenyl-derivative was more than 1,500-fold more active than the original fragment hit (48) with an apparent Ki (Kiapp) of 7 nM and highly selective over both human and T. brucei DHFR.