E-Pharmacophore model-guided design of potential DprE1 inhibitors: synthesis, in vitro antitubercular assay and molecular modelling studies

Avinash Kumar,Suvarna G Kini,Revathi Rajappan,Sriram Dharmarajan,Ekta Rathi,K Sreedhara Ranganath Pai

doi:10.1007/s11696-021-01743-3

Avinash Kumar, Suvarna G Kini + Show 4 more

Open Access

https://doi.org/10.1007/s11696-021-01743-3

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Abstract

Tuberculosis continues to wreak havoc worldwide and caused around 1.4 million deaths in 2019. Hence, in our pursuit of developing novel antitubercular compounds, we are reporting the e-Pharmacophore-based design of DprE1 (decaprenylphosphoryl-ribose 2′-oxidase) inhibitors. In the present work, we have developed a four-feature e-Pharmacophore model based on the receptor–ligand cavity of DprE1 protein (PDB ID 4P8C) and mapped our previous reported library of compounds against it. The compounds were ranked on phase screen score, and the insights obtained from their alignment were used to design some novel compounds. The designed compounds were docked with DprE1 protein in extra-precision mode using Glide module of Maestro, Schrodinger. Some derivatives like B1, B2, B4, B5 and B12 showed comparable docking score (docking score > − 6.0) with respect to the co-crystallized ligand. The designed compounds were synthesized and characterized. In vitro antitubercular activity was carried out on Mycobacterium tuberculosis H37Rv (ATCC27294) strain using the agar dilution method, and minimum inhibitory concentration (MIC) was determined. The compound B12 showed a MIC value of 1.56 μg/ml which was better than the standard drug ethambutol (3.125 μg/ml). Compounds B7 and B11 were found to be equipotent with ethambutol. Cytotoxicity studies against Vero cell lines proved that these compounds were non-cytotoxic. Molecular dynamic simulation study also suggests that compound B12 will form a stable complex with DprE1 protein and will show the crucial H-bond interaction with LYS418 residue. Further in vitro enzyme inhibition studies are required to validate these findings.

Highlights

More than 40 years have passed since the introduction of the quadruple drug therapy regimen for tuberculosis (TB), which has proven to be both effective and cost-effective
We have developed a four-feature e-Pharmacophore model based on the receptor–ligand cavity of DprE1 protein (PDB ID 4P8C) and mapped our previous reported library of compounds against it
The compounds were ranked on phase screen score, and the insights obtained from their alignment was used to design some novel benzimidazole-substituted compounds which might act as DprE1 inhibitors

Summary

Introduction

More than 40 years have passed since the introduction of the quadruple drug therapy regimen for tuberculosis (TB), which has proven to be both effective and cost-effective. TB continues to wreak havoc worldwide which is evident from the fact that worldwide around 1.4 million died of TB in 2019 (Raviglione et al 2012; Global tuberculosis report 2020). This state of high mortality rate feeds on various factors like prolonged duration of antitubercular therapy, toxicity induced by the antitubercular drugs, lower patient compliance and the rise of MDR-TB (multidrugresistant). Bedaquiline, pretomanid and delamanid are the only drugs approved by the FDA (Food and Drug Administration) in the last four decades to treat MDR-TB which highlights the associated challenges in the field of antitubercular drug discovery (Cohen 2013). DPX is further reduced to DPA (decaprenylphosporyl arabinose) by DprE2 as shown in Fig. 1 (Mikušová et al 2005; Brecik et al 2015)

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