New Potential Pharmacological Targets of Plant-Derived Hydroxyanthraquinones from Rubia spp.

The increased use of polyphenols nowadays poses the need for identification of their new pharmacological targets. Recently, structure similarity-based virtual screening of DrugBank outlined pseudopurpurin, a hydroxyanthraquinone from Rubia cordifolia spp., as similar to gatifloxacin, a synthetic antibacterial agent. This suggested the bacterial DNA gyrase and DNA topoisomerase IV as potential pharmacological targets of pseudopurpurin. In this study, estimation of structural similarity to referent antibacterial agents and molecular docking in the DNA gyrase and DNA topoisomerase IV complexes were performed for a homologous series of four hydroxyanthraquinones. Estimation of shape- and chemical feature-based similarity with (S)-gatifloxacin, a DNA gyrase inhibitor, and (S)-levofloxacin, a DNA topoisomerase IV inhibitor, outlined pseudopurpurin and munjistin as the most similar structures. The docking simulations supported the hypothesis for a plausible antibacterial activity of hydroxyanthraquinones. The predicted docking poses were grouped into 13 binding modes based on spatial similarities in the active site. The simultaneous presence of 1-OH and 3-COOH substituents in the anthraquinone scaffold were emphasized as relevant features for the binding modes’ variability and ability of the compounds to strongly bind in the DNA-enzyme complexes. The results reveal new potential pharmacological targets of the studied polyphenols and help in their prioritization as drug candidates and dietary supplements.

[1]  K. Neuman,et al.  DNA topoisomerases: Advances in understanding of cellular roles and multi-protein complexes via structure-function analysis , 2021, BioEssays : news and reviews in molecular, cellular and developmental biology.

[2]  P. Bednář,et al.  Study of Tetrahydroxylated Anthraquinones—Potential Tool to Assess Degradation of Anthocyanins Rich Food , 2020, Molecules.

[3]  L. Di Marcotullio,et al.  Dual SMO/BRAF Inhibition by Flavonolignans from Silybum marianum † , 2020, Antioxidants.

[4]  I. Pajeva,et al.  In silico and in vivo studies of Astragalus glycyphylloides saponin(s) with relevance to metabolic syndrome modulation. , 2019, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[5]  Jian-Guo Jiang,et al.  Health functions and structure-activity relationships of natural anthraquinones from plants. , 2018, Food & function.

[6]  T. V. van Beek,et al.  Comparison of madder (Rubia tinctorum L.) and weld (Reseda luteola L.) total extracts and their individual dye compounds with regard to their dyeing behaviour, colour, and stability towards light , 2018, Coloration Technology.

[7]  Todd R. Wiernicki,et al.  Identification of Compounds with pH-Dependent Bactericidal Activity against Mycobacterium tuberculosis , 2018, ACS infectious diseases.

[8]  R. Blackburn.  Natural dyes in madder (Rubia spp.) and their extraction and analysis in historical textiles , 2017 .

[9]  David S. Wishart,et al.  DrugBank 5.0: a major update to the DrugBank database for 2018 , 2017, Nucleic Acids Res..

[10]  L. Dufossé,et al.  Natural hydroxyanthraquinoid pigments as potent food grade colorants: an overview , 2012, Natural Products and Bioprospecting.

[11]  P. Boriack-Sjodin,et al.  Discovery of a novel azaindole class of antibacterial agents targeting the ATPase domains of DNA gyrase and Topoisomerase IV. , 2012, Bioorganic & medicinal chemistry letters.

[12]  Benjamin A. Ellingson,et al.  Conformer Generation with OMEGA: Algorithm and Validation Using High Quality Structures from the Protein Databank and Cambridge Structural Database , 2010, J. Chem. Inf. Model..

[13]  D. Schnappinger,et al.  A membrane protein preserves intrabacterial pH in intraphagosomal Mycobacterium tuberculosis , 2008, Nature Medicine.

[14]  P. Hawkins,et al.  Comparison of shape-matching and docking as virtual screening tools. , 2007, Journal of medicinal chemistry.

[15]  Sang-Woon Choi,et al.  DNA Topoisomerases I and II Inhibition and Cytotoxicity of Constituents from the Roots of Rubia cordifolia. , 2007 .

[16]  H. Corke,et al.  Structure-radical scavenging activity relationships of phenolic compounds from traditional Chinese medicinal plants. , 2006, Life sciences.

[17]  B. Hazra,et al.  Evaluation of the antibacterial activity of Ventilago madraspatana Gaertn., Rubia cordifolia Linn. and Lantana camara Linn.: isolation of emodin and physcion as active antibacterial agents , 2005, Phytotherapy research : PTR.

[18]  J. Novak,et al.  Alterations in DNA Gyrase and Topoisomerase IV in Resistant Mutants of Clostridium perfringens Found after In Vitro Treatment with Fluoroquinolones , 2005, Antimicrobial Agents and Chemotherapy.

[19]  R. Finberg,et al.  Quinolones , 2021, Clinical Use of Anti-infective Agents.

[20]  I. Pajeva,et al.  Estimation of structural similarity between plant-derived phenolic compounds and drug molecules by virtual screening of DrugBank , 2020 .

[21]  M. Hosaka.  [Antibacterial property and clinical effect of gatifloxacin, a novel quinolone antibacterial agent]. , 2003, Nihon yakurigaku zasshi. Folia pharmacologica Japonica.

[22]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..