A census of P. longum’s phytochemicals and their network pharmacological evaluation for identifying novel drug-like molecules against various diseases, with a special focus on neurological disorders

RESEARCH ARTICLE A census of P. longum’s phytochemicals and their network pharmacological evaluation for identifying novel drug-like molecules against various diseases, with a special focus on neurological disorders Neha Choudhary, Vikram Singh* a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 Centre for Computational Biology and Bioinformatics, School of Life Sciences, Central University of Himachal Pradesh, Himachal Pradesh, India * Abstract OPEN ACCESS Citation: Choudhary N, Singh V (2018) A census of P. longum’s phytochemicals and their network pharmacological evaluation for identifying novel drug-like molecules against various diseases, with a special focus on neurological disorders. PLoS ONE 13(1): e0191006. https://doi.org/10.1371/ journal.pone.0191006 Editor: Hiroyoshi Ariga, Hokkaido Daigaku, JAPAN Received: October 15, 2017 Accepted: December 25, 2017 Published: January 10, 2018 Copyright: © 2018 Choudhary, Singh. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Piper longum (P. longum, also called as long pepper) is one of the common culinary herbs that has been extensively used as a crucial constituent in various indigenous medicines, specifically in traditional Indian medicinal system known as Ayurveda. For exploring the comprehensive effect of its constituents in humans at proteomic and metabolic levels, we have reviewed all of its known phytochemicals and enquired about their regulatory potential against various protein targets by developing high-confidence tripartite networks consisting of phytochemical—protein target—disease association. We have also (i) studied immunomodulatory potency of this herb; (ii) developed subnetwork of human PPI regulated by its phytochemicals and could successfully associate its specific modules playing important role in diseases, and (iii) reported several novel drug targets. P10636 (microtubule-associated protein tau, that is involved in diseases like dementia etc.) was found to be the commonly screened target by about seventy percent of these phytochemicals. We report 20 drug-like phytochemicals in this herb, out of which 7 are found to be the potential regulators of 5 FDA approved drug targets. Multi-targeting capacity of 3 phytochemicals involved in neuroactive ligand receptor interaction pathway was further explored via molecular docking experiments. To investigate the molecular mechanism of P. longum’s action against neurological disorders, we have developed a computational framework that can be easily extended to explore its healing potential against other diseases and can also be applied to scrutinize other indigenous herbs for drug-design studies. Funding: The authors received no specific funding for this work. Competing interests: The authors have declared that no competing interests exist. Introduction Abbreviations: ADMET, Absorption, Distribution, Metabolism, Excretion and Toxicity; BP, Biological pathways; DA, Disease association; GPCR, G Healing with medicinal plants is an ancient idea. Secondary metabolites of various plants have been traditionally utilized for the betterment of human health. Plants belonging to genus Piper are amongst the most important medicinal plants used in various systems of medicine. More PLOS ONE | https://doi.org/10.1371/journal.pone.0191006 January 10, 2018 1 / 31 Network pharmacological evaluation of Piper longum protein-coupled receptors; P. longum, Piper longum; PC, Phytochemical; PCt, Number of protein targets corresponding to a particular phytochemical; PPI, Protein protein interactions; PT, Protein target; Tt, Total number of protein targets of P. longum. than 1,000 species belong to this genus and P. longum is one of the most well-known species amongst them, including Piper nigrum and Piper bettle. P. longum forms an active constituent of the widely used Ayurvedic poly-herbal formulation “Trikatu” [1]. The widespread use of this herb in different formulations as documented in ancient Ayurvedic manuscripts such as Caraka samhita [2], Susruta samhita [3] Vagbhata’s astanga hrdayam [4] etc. suggests its vital importance in traditional Indian medicinal system. P. longum is an indigenously growing plant in India and is also cultivated in the tropical and subtropical regions of Asia and Pacific islands [5]. It is usually cultivated for its fruit which is dried and used as a spice. The plant grows into a shrub with large woody roots, numerous creeping and jointed stems that are thickened at the nodes. Leaves are without stipules and spreading in nature. Fruits are small, oval shaped berries and grow as spikes that are collected after maturation. Dried form of these spikes makes “pippali” while the root radix is known as “pippalimula”. The dietary piperine is known for its bioavailability and digestion enhancing properties. In vitro studies have shown the role of piperine in relieving oxidative stress by quenching free radicals and reactive oxygen species. While it is known to act as an anti-mutagenic and anti-tumor agent [6], anti-diarrheic and anti-dysenteric properties of this spice enhance its medicinal value [7]. The pharmacological properties of this plant also include antioxidant, anti-inflammatory, hepatoprotective, immunomodulatory, anti-microbial, anti-platelet, anti-hyperlipidemic, analgesic, anti-depressant, anti-amoebic, anti-obesity, radioprotective, cardioprotective and anti-fungal [8], [9], [10], [11]. Methanolic extract of this fruit has been reported to be involved in memory repair and improving memory performance by an in vitro model [12]. Clinical studies have revealed the efficacy of this plant in the treatment of bronchial asthma in children [13], [14]. Anti-diabetic activity of the roots has also been reported [15]. It is widely used as an important constituent in various Ayurvedic medicines to cure diseases like leprosy and tuberculosis and is also used in the treatment of cough, dyspnea, cardiac and spleen disorders, chronic-fever, gout, rheumatic pain etc. [16]. In recent years, the advancement in chemistry, pharmacology and systems biology has created a new paradigm for the drug discovery known as network pharmacology [17]. Integration of traditional knowledge of medicines with recent in silico approaches has led to the identification of novel natural drug compounds. The approach has recently gathered much attention by the research community as network pharmacology based studies have been widely used to explore the medicinal activities of herbs like Withania somnifera [18] and formulae like QiShenYiQi [19], Gegen Qinlian decoction [20] etc. to understand their molecular level effect in the treatment of syndromes or diseases. In the present w (...truncated)