Potential Inhibitors of Galactofuranosyltransferase 2 (GlfT2): Molecular Docking, 3D-QSAR, and In Silico ADMETox Studies

Christopher Llynard D Ortiz,Ricky B Nellas,Ruel C Nacario,Gladys C Completo

doi:10.1038/s41598-019-52764-8

Christopher Llynard D Ortiz, Ricky B Nellas + Show 2 more

Open Access

https://doi.org/10.1038/s41598-019-52764-8

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Abstract

A strategy in the discovery of anti-tuberculosis (anti-TB) drug involves targeting the enzymes involved in the biosynthesis of Mycobacterium tuberculosis’ (Mtb) cell wall. One of these enzymes is Galactofuranosyltransferase 2 (GlfT2) that catalyzes the elongation of the galactan chain of Mtb cell wall. Studies targeting GlfT2 have so far produced compounds showing minimal inhibitory activity. With the current challenge of designing potential GlfT2 inhibitors with high inhibition activity, computational methods such as molecular docking, receptor-ligand mapping, molecular dynamics, and Three-Dimensional-Quantitative Structure-Activity Relationship (3D-QSAR) were utilized to deduce the interactions of the reported compounds with the target enzyme and enabling the design of more potent GlfT2 inhibitors. Molecular docking studies showed that the synthesized compounds have binding energy values between −3.00 to −6.00 kcal mol−1. Two compounds, #27 and #31, have registered binding energy values of −8.32 ± 0.01, and −8.08 ± 0.01 kcal mol−1, respectively. These compounds were synthesized as UDP-Galactopyranose mutase (UGM) inhibitors and could possibly inhibit GlfT2. Interestingly, the analogs of the known disaccharide substrate, compounds #1–4, have binding energy range of −10.00 to −19.00 kcal mol−1. The synthesized and newly designed compounds were subjected to 3D-QSAR to further design compounds with effective interaction within the active site. Results showed improved binding energy from −6.00 to −8.00 kcal mol−1. A significant increase on the binding affinity was observed when modifying the aglycon part instead of the sugar moiety. Furthermore, these top hit compounds were subjected to in silico ADMETox evaluation. Compounds #31, #70, #71, #72, and #73 were found to pass the ADME evaluation and throughout the screening, only compound #31 passed the predicted toxicity evaluation. This work could pave the way in the design and synthesis of GlfT2 inhibitors through computer-aided drug design and can be used as an initial approach in identifying potential novel GlfT2 inhibitors with promising activity and low toxicity.

Highlights

Mycobacterium species’ cell wall acts as a rigid scaffold that hinders the penetrating action of antibiotics
Docking studies were performed on these compounds and the results showed that trisaccharides, compounds #55 and #56, have lower binding energy values (−6.24 ± 0.04 and −6.19 ± 0.04 kcal mol−1, respectively) compared with disaccharides, compounds #53 and #54 (−6.16 ± 0.03 and −6.11 ± 0.03 kcal mol−1, respectively) (Table 13)
The structures of the presented synthesized Galactofuranosyltransferase 2 (GlfT2) inhibitors were aligned along their respective molecular field points

Summary

Introduction

Mycobacterium species’ cell wall acts as a rigid scaffold that hinders the penetrating action of antibiotics. The drawback of using the aforementioned compounds is in their inability to pass through the cell membrane because of the polar sugar moiety and charged diphosphate group Another strategy was proposed by replacing the diphosphate group of UDP-Galf with basic amino acids such as lysine, glutamine, tryptophan, and histidine. Among the four sugar-amino acid-nucleosides, those with tryptophan and histidine as the replacement for the diphosphate moiety have shown 30% and 37% inhibition activity with GlfT223, respectively. Another series of GlfT2’s donor-mimicking inhibitors are compounds #15–18 (Fig. 1). These are structurally described as imino-galactofuranose sugar moieties with uridine as an aglycon. It was found that only compound #18 exhibited less than 35% inhibition activity against UGM26

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Conclusion