Toward α‐1,3/4 fucosyltransferases targeted drug discovery: In silico uncovering of promising natural inhibitors of fucosyltransferase 6

Abstract

Sialyl Lewis X (sLex) antigen is a fucosylated cell‐surface glycan that is normally involved in cell‐cell interactions. The enhanced expression of sLex on cell surface glycans, which is attributed to the upregulation of fucosyltransferase 6 (FUT6), has been implicated in facilitating metastasis in human colorectal, lung, prostate, and oral cancers. The role that the upregulated FUT6 plays in the progression of tumor to malignancy, with reduced survival rates, makes it a potential target for anticancer drugs. Unfortunately, the lack of experimental structures for FUT6 has hampered the design and development of its inhibitors. In this study, we used in silico techniques to identify potential FUT6 inhibitors. We first modeled the three‐dimensional structure of human FUT6 using AlphaFold. Then, we screened the natural compound libraries from the COCONUT database to sort out potential natural products (NPs) with best affinity toward the FUT6 model. As a result of these simulations, we identified three NPs for which we predicted binding affinities and interaction patterns quite similar to those we calculated for two experimentally tested FUT6 inhibitors, that is, fucose mimetic‐1 and a GDP‐triazole derived compound. We also performed molecular dynamics (MD) simulations for the FUT6 complexes with identified NPs, to investigate their stability. Analysis of the MD simulations showed that the identified NPs establish stable contacts with FUT6 under dynamics conditions. On these grounds, the three screened compounds appear as promising natural alternatives to experimentally tested FUT6 synthetic inhibitors, with expected comparable binding affinity. This envisages good prospects for future experimental validation toward FUT6 inhibition.

Succinimide Derivatives as Acetylcholinesterase Inhibitors—In Silico and In Vitro Studies

“…ADMETlab 3.0 was employed to calculate descriptors associated with absorption, distribution, metabolism, toxicity, excretion, and the human intestinal absorption of (I) and (II) [ 60 ]. Those results can be found in Supplementary Files S1 and S2 , respectively.…”

“…In addition, the hydrogen bond with the amino acid SER 293 may have an impact on the stability of the protein-ligand interaction because of the imide substituent that is present (Figure 5). ADMETlab 3.0 was employed to calculate descriptors associated with absorption, distribution, metabolism, toxicity, excretion, and the human intestinal absorption of (I) and (II) [60]. Those results can be found in Supplementary Files S1 and S2, respectively.…”

Designing and Exploration of the Biological Potentials of Novel Centrosymmetric Heteroleptic Copper(II) Carboxylates

“…Table 8 presents the physicochemical parameters including solubility, lipophilicity, toxicity risks, drug-likeness, pharmacokinetics and medicinal chemistry of the synthesized compounds, evaluated according to the following filters: Lipinski [30], Ghose [31], Veber [32], Egan [33] and Muegge [34] using the SwissADME server [35]. An orally-active compound should follow these filters and should not have more than one violation.…”

“…The predicted numbers of rotatable bonds were in the range of 2-10. The total surface area (tPSA) due to polar atoms of a molecule is used to determine the drug transport parameters [35] and compounds with a smaller tPSA value have greater drug transport potential. The tPSA values for the synthesized compounds are as follows: HL (37.00 Å 2 ) and 1-2 (73.21 Å 2 ).…”

“…H-bond acceptors < 10, No. H-bond donor < 5) [35]. Figure 8 represents the bioavailability radar image of HL and complex 1.…”