Binding mode analysis of dual inhibitors of human thymidylate synthase and dihydrofolate reductase as antitumour agents via molecular docking and DFT studies

Trypanothione reductase (TryR) is a key enzyme in the metabolism of Trypanosoma cruzi, the parasite responsible for Chagas disease. The available repertoire of TryR inhibitors relies heavily on synthetic substrates of limited structural diversity, and less on plant-derived natural products. In this study, a molecular docking procedure using a Lamarckian Genetic Algorithm was implemented to examine the protein-ligand binding interactions of strong in vitro inhibitors for which no X-ray data is available. In addition, a small, skeletally diverse, set of natural alkaloids was assessed computationally against T. cruzi TryR in search of new scaffolds for lead development. The preferential binding mode (low number of clusters, high cluster population), together with the deduced binding interactions were used to discriminate among the virtual inhibitors. This study confirms the prior in vitro data and proposes quebrachamine, cephalotaxine, cryptolepine, (22 S,25 S)-tomatidine, (22 R,25 S)-solanidine, and (22 R,25 R)-solasodine as new alkaloid scaffold leads in the search for more potent and selective TryR inhibitors.

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Evidence of Pyrimethamine and Cycloguanil Analogues as Dual Inhibitors of Trypanosoma brucei Pteridine Reductase and Dihydrofolate Reductase

Pharmaceuticals ◽

10.3390/ph14070636 ◽

2021 ◽

Vol 14 (7) ◽

pp. 636

Author(s):

Giusy Tassone ◽

Giacomo Landi ◽

Pasquale Linciano ◽

Valeria Francesconi ◽

Michele Tonelli ◽

...

Keyword(s):

Trypanosoma Brucei ◽

Dihydrofolate Reductase ◽

Neglected Tropical Diseases ◽

Binding Mode ◽

Structural Features ◽

Binding Modes ◽

Substitution Pattern ◽

Future Design ◽

Dual Inhibitors ◽

Etiological Agents

Trypanosoma and Leishmania parasites are the etiological agents of various threatening neglected tropical diseases (NTDs), including human African trypanosomiasis (HAT), Chagas disease, and various types of leishmaniasis. Recently, meaningful progresses in the treatment of HAT, due to Trypanosoma brucei (Tb), have been achieved by the introduction of fexinidazole and the combination therapy eflornithine–nifurtimox. Nevertheless, due to drug resistance issues and the exitance of animal reservoirs, the development of new NTD treatments is still required. For this purpose, we explored the combined targeting of two key folate enzymes, dihydrofolate reductase (DHFR) and pteridine reductase 1 (PTR1). We formerly showed that the TbDHFR inhibitor cycloguanil (CYC) also targets TbPTR1, although with reduced affinity. Here, we explored a small library of CYC analogues to understand how their substitution pattern affects the inhibition of both TbPTR1 and TbDHFR. Some novel structural features responsible for an improved, but preferential, ability of CYC analogues to target TbPTR1 were disclosed. Furthermore, we showed that the known drug pyrimethamine (PYR) effectively targets both enzymes, also unveiling its binding mode to TbPTR1. The structural comparison between PYR and CYC binding modes to TbPTR1 and TbDHFR provided key insights for the future design of dual inhibitors for HAT therapy.

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