Dataset Information

Fucosyltransferase 2 inhibitors: Identification via docking and STD-NMR studies.

ABSTRACT: Fucosyltransferase 2 (FUT2) catalyzes the biosynthesis of A, B, and H antigens and other important glycans, such as (Sialyl Lewisx) sLex, and (Sialyl Lewisy) sLey. The production of these glycans is increased in various cancers, hence to design and develop specific inhibitors of FUT2 is a therapeutic strategy. The current study was designed to identify the inhibitors for FUT2. In silico screening of 300 synthetic compounds was performed. Molecular docking studies highlighted the interactions of ligands with critical amino acid residues, present in the active site of FUT2. The epitope mapping in ligands was performed using the STD-NMR experiments to identify the interactions between ligands, and receptor protein. Finally, we have identified 5 lead compounds 4, 5, 26, 27, and 28 that can be studied for further development as cancer therapeutic agents.

SUBMITTER: Zafar H

PROVIDER: S-EPMC8516197 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Fucosyltransferase 2 inhibitors: Identification via docking and STD-NMR studies.

Zafar Humaira H Atif Muhammad M Atia-Tul-Wahab Choudhary M Iqbal MI

PloS one 20211014 10

Fucosyltransferase 2 (FUT2) catalyzes the biosynthesis of A, B, and H antigens and other important glycans, such as (Sialyl Lewisx) sLex, and (Sialyl Lewisy) sLey. The production of these glycans is increased in various cancers, hence to design and develop specific inhibitors of FUT2 is a therapeutic strategy. The current study was designed to identify the inhibitors for FUT2. In silico screening of 300 synthetic compounds was performed. Molecular docking studies highlighted the interactions of ...[more]

PMID: 34648519

Similar Datasets

Project description:Background/Objectives: Pteridine reductase 1 (PTR1) has been one of the prime targets for discovering novel antileishmanial therapeutics in the fight against Leishmaniasis. This enzyme catalyzes the NADPH-dependent reduction of pterins to their tetrahydro forms. While chemotherapy remains the primary treatment, its effectiveness is constrained by drug resistance, unfavorable side effects, and substantial associated costs. Methods: This study addresses the urgent need for novel, cost-effective drugs by employing in silico techniques to identify potential lead compounds targeting the PTR1 enzyme. A library of 1463 natural compounds from AfroDb and NANPDB, prefiltered based on Lipinski's rules, was used to screen against the LmPTR1 target. The X-ray structure of LmPTR1 complexed with NADP and dihydrobiopterin (Protein Data Bank ID: 1E92) was identified to contain the critical residues Arg17, Leu18, Ser111, Phe113, Pro224, Gly225, Ser227, Leu229, and Val230 including the triad of residues Asp181-Tyr194-Lys198, which are critical for the catalytic process involving the reduction of dihydrofolate to tetrahydrofolate. Results: The docking yielded 155 compounds meeting the stringent criteria of -8.9 kcal/mol instead of the widely used -7.0 kcal/mol. These compounds demonstrated binding affinities comparable to the known inhibitors; methotrexate (-9.5 kcal/mol), jatrorrhizine (-9.0 kcal/mol), pyrimethamine (-7.3 kcal/mol), hardwickiic acid (-8.1 kcal/mol), and columbamine (-8.6 kcal/mol). Protein-ligand interactions and molecular dynamics (MD) simulation revealed favorable hydrophobic and hydrogen bonding with critical residues, such as Lys198, Arg17, Ser111, Tyr194, Asp181, and Gly225. Crucial to the drug development, the compounds were physiochemically and pharmacologically profiled, narrowing the selection to eight compounds, excluding those with potential toxicities. The five selected compounds ZINC000095486253, ZINC000095486221, ZINC000095486249, 8alpha-hydroxy-13-epi-pimar-16-en-6,18-olide, and pachycladin D were predicted to be antiprotozoal (Leishmania) with Pa values of 0.642, 0.297, 0.543, 0.431, and 0.350, respectively. Conclusions: This study identified five lead compounds that showed substantial binding affinity against LmPTR1 as well as critical residue interactions. A 100 ns MD combined with molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations confirmed the robust binding interactions and provided insights into the dynamics and stability of the protein-ligand complexes.

Dataset Information

Fucosyltransferase 2 inhibitors: Identification via docking and STD-NMR studies.

Publications

Fucosyltransferase 2 inhibitors: Identification via docking and STD-NMR studies.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets