Comparative In Silico Molecular Docking Analysis of L-Threonine-3-Dehydrogenase, a Protein Target Against African Trypanosomiasis Using Selected Phytochemicals

Abstract

Introduction: African trypanosomiasis is a neglected tropical disease caused by protozoa Trypanosoma brucei and transmitted via the bite of tsetse fly. The target protein of T. brucei is L-threonine-3-dehydrogenase, which has been selected for this study due to its metabolic importance for the parasite's survival. Docking of target protein was carried out with phytochemicals that passed in silico drug-likeness filters and have in vitro antitrypanosomal activity along with the standard drugs eflornithine and pentamidine available against the disease. Materials and Methods: A 3D structure of L-threonine-3-dehyrogenase was downloaded from Protein Data Bank (PDB) with Id: 5K4Y and Pictorial database of 3D structures in the Protein Data Bank (PDBsum) was used to retrieve the active sites of the protein. The reviewed ligands were screened using SwissADME, Lipinski's rule of 5, and Molinspiration servers along with standard drugs and docked using AutoDock Vina and AutoDock 4.2.6. The 2D and 3D interacting residues were observed using Discovery Studio. Results: Ligand Camptothecin which inhibited T. brucei during in vitro cytotoxic assays gave better binding affinity scores than the standard drugs (eflornithine and pentamidine) selected for this study. Camptothecin showed interaction with those active site residues where ligand NAD (nicotinamide-adenine-dinucleotide) binds to the target protein, which is a significant restricting pocket for the hindrance of the parasite. Conclusions: Camptothecin derived from Camptotheca acuminata trees has the potential to be used as a better alternative than the standard drugs because of its less toxicity, better binding affinity, and specificity towards the inhibition of target protein.

Potential of Plant Bioactive Compounds as SARS-CoV-2 Main Protease (Mpro) and Spike (S) Glycoprotein Inhibitors: A Molecular Docking Study

“…The results of the interaction between the S protein and the selected ligands show that there are unfavorable donor-donor bonds, which means that this bond shows the repulsive force between the two molecules. The formation of this bond can reduce the stability of other types of bonds so that it can affect the stability of the ligands that will be used as drug candidates [ 91 ]. The ligands with this type of bond are hesperidin and pectolinarin, located in the residue Arg-A: 1039 and Arg-B: 1039.…”

Tackling the Moving Mutant Target: Taxifolin Derivatives as Novel Putative E571K Exportin-1 Inhibitors for KRAS-mutant Lung Adenocarcinoma Therapy

“…It is also noteworthy that taxifolin formed additional conventional hydrogen bond (comparably to KPT-185) with the active site serine residue 467, albeit with additional unfavourable donor-donor bond (Figure 3A) that may however potentially affects the drug-like entity activity stability through repulsive reduction of the ligand-protein complex as deduced by Samant et al (2019) 90 . Hydrogen bonding interactions (between the E571K Exportin-1 active site lysine 360, aspartate 460, serine 467 residues and the atomic partial charges of taxifolin, compound 54, as well as KPT-185 in this study(Figure 3)) positively associates90 with significant target-ligand complex stability and bioactivity of the drug-like entities at the target active site. Furthermore, the hydrophobic interactions(Figure 3) of the drug-like entities possess significant putative contributory role in entropy increase-mediated overall binding energy elevation, through displacement of water molecules in ordered layers within 3Å of E571K…”

AVALIAÇÃO DO POTENCIAL ANTI-TIROSINASE E CITOTÓXICO DE EXTRATOS DE <u>Pimenta pseudocaryophyllus</u> (GOMES) LANDRUM

“…2a-c), o que pode afetar a estabilidade da atividade inibitória, já que esse tipo de ligação indica força de repulsão. 7 Entretanto, para eugenol foram identificadas duas ligações hidrogênio envolvendo os N da cadeia lateral de His 61 e His 85 e a hidroxila fenólica do ligante, o que contribui para o aumento do grau de afinidade deste composto para o sítio de ligação (Fig. 2d).…”