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Hydrochlorothiazide and Indapamide bind the NADPH binding site of bacterial Dihydrofolate Reductase: results of an in-silico study and their implications

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Abstract

Hypertension is a public health concern. Low dose thiazide diuretics are known to effectively control blood pressure compared to that of other classes of antihypertensive drugs. In this context, we have performed an in-silico study and found that the two Sulphonamide Diuretics Hydrochlorothiazide and Indapamide bound the NADPH binding region of bacterial Dihydrofolate Reductase. Therefore, akin to Sulphonamide Antibiotics, Sulphonamide Diuretics may have antibiotic activity and thereby have the potential to modulate the gut microbiome in a way beneficial to vascular health. The in-silico experiment results were analyzed in the context of the relevant literature. We postulate that Sulphonamide Diuretics exert their antihypertensive role by modulating the gut microbiome, specifically by increasing butyrate-producing taxa in the gut. We recommend extending such work as it is plausible that Indapamide and other Sulphonamide Diuretics may be beneficial for both diabetes and hypertension.

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Acknowledgements

SK and DB acknowledge PGIMER, Chandigarh for providing financial assistance vide Endst No. PGI/MERC/2020/4655-58 dated 7.10.2019 (Collectively) and No. 71/2-Edu-16/415 dated 23.1.2019.

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Authors and Affiliations

  1. Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India

    Sumanpreet Kaur, Rajasri Bhattacharyya & Dibyajyoti Banerjee

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  1. Sumanpreet Kaur
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  2. Rajasri Bhattacharyya
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  3. Dibyajyoti Banerjee
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Correspondence to Rajasri Bhattacharyya or Dibyajyoti Banerjee.

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40203_2020_56_MOESM1_ESM.tif

S1. Molecular Dynamics (MD) simulation results of the DHFR-Drug complexes after 10 ns are presented. The codes of different drugs used in the graphs are et- Ethacrynic acid, sd- Sulphadiazine, in- Indapamide and hy- Hydrochlorothiazide

40203_2020_56_MOESM2_ESM.tif

S2. The superposed drug-DHFR complexes ((a)-Ethacrynic, (b)-Sulphadiazine, (c)-Indapamide and (d)-Hydrochlorothiazide) after docking and Molecular Dynamic (MD) simulation are shown. After docking in cyan cartoon – DHFR and red stick – drug, while after MD simulation in silver cartoon – DHFR and blue stick – drug are shown

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Kaur, S., Bhattacharyya, R. & Banerjee, D. Hydrochlorothiazide and Indapamide bind the NADPH binding site of bacterial Dihydrofolate Reductase: results of an in-silico study and their implications. In Silico Pharmacol. 8, 5 (2020). https://doi.org/10.1007/s40203-020-00056-9

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