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IN SILICO SCREENING OF SOME PLANT BASED NATURAL PRODUCTS AS ANGIOTENSIN RECEPTOR BLOCKERS AGAINST CARDIOVASCULAR DISEASES
Abstract and Figures
Many plants have been listed in the traditional systems of medicine and some of these are providing comprehensive relief to the people suffering from cardio-vascular diseases (CVD) and are recognized for their ability to produce secondary metabolites. Secondary metabolites obtained from different plants have been the starting material for designing different drugs. Many phytochemicals exert cardiovascular actions and paved the path towards development of cardioprotective formulations. In the present study we have analyzed the inhibitory potential of some plant based natural products on the Angiotensin II Type 1 (AT1) Receptor - the enzyme responsible for various cardiovascular diseases. Binding affinity of the compounds against
known cardioprotective drug target was calculated by performing the docking experiment using FlexX. Toxicity screening revealed that phytochemicals were non-toxic and obeyed Lipinski’s rule. The docking studies showed greater affinity of the phytochemicals – Morin and Orotic acid towards the active site of drug target. The study suggests that the phytochemicals – Morin and Orotic acid may be Angiotensin II Type 1 (AT1) Receptor targeted potent new drug for treating Cardiovascular diseases.
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More than 2000 plants have been listed in the Traditional (Herbal/Alternative) systems of medicine and some of these are providing comprehensive relief to the people suffering from cardio-vascular diseases, specially “hyperlipidemia” and “ischemic heart disease”. WHO reports indicate that around eighty percent of the global population still relies on botanical drugs and several herbal medicines have advanced to clinical use in modern times. Several medicinal plants have been described to be beneficial for cardiac ailments in “Atharva Veda” Quite a few of them, for example, Allium sativum L. (Garlic), Cicer arietinum L. (Bengal gram), Commiphora mukul Engl. (Guggul), Curcuma longa L. (Turmeric), Eugenia jambolana Willd. (Jamun), Emblica officinalis Gaertn. (Goose berry), Ocimum sanctum L. (Tulsi), Terminalia arjuna Wight & Arn. (Arjuna) and Trigonella foenum-graecum L. (Fenugreek) have been identified and researched for their putative lipid lowering and cardioprotective activities. The plant which has shown most promising and distinct results among these is Terminalia arjuna Wight & Arn., popularly known as Arjuna. Many phytochemical have been isolated from different plant parts having cardioprotective activities. Based on these findings, present review is written to identify the plant based cardioprotective natural products.
There are few natural products analgesics which target TRPV1. Solanoglycosydane a glucosidal steroid isolated from the tender fruits of the plant Solanum torvum Swartz reported to have analgesic action. But molecular mechanism of action of this product in inducing analgesic action was not explained. In the present work we wanted to see if the analgesic action of Solanoglycosydane is mediated through TRPV1 using computational tool. The three dimensional structure of TRPV1 was downloaded from Protein Data Bank (RCSB PDB). The molecule was analyzed to find its probable active site using online server, Q-Site Finder. This program depicts the amino acids of the probable ligand binding sites of the enzyme. The very first site was selected as it was the energetically most favorable. The three dimensional structure of Solanoglycosydane was generated using another online server, CORINA. This structure of Solanoglycosydane was also saved in PDB format and is converted to sdf format using OpenBabel. The ADME/Tox properties of the compound were also studied using Mobyle ADME/Tox server. To study the binding efficacy of Solanoglycosydane to TRPV1, FlexX was used. The ADME/Tox screenings of Solanoglycosydane have not shown any negative results, which indicate the potentiality of the molecule to become drugs. The compound showed greater binding affinity towards TRPV1. The study suggested that Solanoglycosydane induces analgesic action by inhibiting TRPV1.
Background:
Ischaemic heart disease (IHD) is the leading cause of death worldwide. The World Health Organisation (WHO) collects mortality data coded using the International Statistical Classification of Diseases (ICD) code.
Methods:
We analysed IHD deaths world-wide between 1995 and 2009 and used the UN population database to calculate age-specific and directly and indirectly age-standardised IHD mortality rates by country and region.
Results:
IHD is the single largest cause of death worldwide, causing 7,249,000 deaths in 2008, 12.7% of total global mortality. There is more than 20-fold variation in IHD mortality rates between countries. Highest IHD mortality rates are in Eastern Europe and Central Asian countries; lowest rates in high income countries. For the working-age population, IHD mortality rates are markedly higher in low-and-middle income countries than in high income countries. Over the last 25 years, age-standardised IHD mortality has fallen by more than half in high income countries, but the trend is flat or increasing in some low-and-middle income countries. Low-and-middle income countries now account for more than 80% of global IHD deaths.
Conclusions:
The global burden of IHD deaths has shifted to low-and-middle income countries as lifestyles approach those of high income countries. In high income countries, population ageing maintains IHD as the leading cause of death. Nevertheless, the progressive decline in age-standardised IHD mortality in high income countries shows that increasing IHD mortality is not inevitable. The 20-fold mortality difference between countries, and the temporal trends, may hold vital clues for handling IHD epidemic which is migratory, and still burgeoning.
The mechanisms of regulation, activation and signal transduction of the angiotensin II (Ang II) type 1 (AT1) receptor have been studied extensively in the decade after its cloning. The AT1 receptor is a major component of the renin-angiotensin system (RAS). It mediates the classical biological actions of Ang II. Among the structures required for regulation and activation of the receptor, its carboxyl-terminal region plays crucial roles in receptor internalization, desensitization and phosphorylation. The mechanisms involved in heterotrimeric G-protein coupling to the receptor, activation of the downstream signaling pathway by G proteins and the Ang II signal transduction pathways leading to specific cellular responses are discussed. In addition, recent work on the identification and characterization of novel proteins associated with carboxyl-terminus of the AT1 receptor is presented. These novel proteins will advance our understanding of how the receptor is internalized and recycled as they provide molecular mechanisms for the activation and regulation of G-protein-coupled receptors.Keywords: RAS, Ang II, receptor, internalization, recycling, yeast two-hybrid system
ABSTRACT:
A frequent problem in computational modeling is the interconversion of chemical structures between different formats. While standard interchange formats exist (for example, Chemical Markup Language) and de facto standards have arisen (for example, SMILES format), the need to interconvert formats is a continuing problem due to the multitude of different application areas for chemistry data, differences in the data stored by different formats (0D versus 3D, for example), and competition between software along with a lack of vendor-neutral formats.
We discuss, for the first time, Open Babel, an open-source chemical toolbox that speaks the many languages of chemical data. Open Babel version 2.3 interconverts over 110 formats. The need to represent such a wide variety of chemical and molecular data requires a library that implements a wide range of cheminformatics algorithms, from partial charge assignment and aromaticity detection, to bond order perception and canonicalization. We detail the implementation of Open Babel, describe key advances in the 2.3 release, and outline a variety of uses both in terms of software products and scientific research, including applications far beyond simple format interconversion.
Open Babel presents a solution to the proliferation of multiple chemical file formats. In addition, it provides a variety of useful utilities from conformer searching and 2D depiction, to filtering, batch conversion, and substructure and similarity searching. For developers, it can be used as a programming library to handle chemical data in areas such as organic chemistry, drug design, materials science, and computational chemistry. It is freely available under an open-source license from http://openbabel.org.
The FAF-Drugs2 server is a web application that prepares chemical compound libraries prior to virtual screening or that assists hit selection/lead optimization before chemical synthesis or ordering. The FAF-Drugs2 web server is an enhanced version of the FAF-Drugs2 package that now includes Pan Assay Interference Compounds detection. This online toolkit has been designed through a user-centered approach with emphasis on user-friendliness. This is a unique online tool allowing to prepare large compound libraries with in house or user-defined filtering parameters.
Availability:
The FAF-Drugs2 server is freely available at http://bioserv.rpbs.univ-paris-diderot.fr/FAF-Drugs/.
Highly selective angiotensin II (Ang II) type 1 (AT(1)) receptor blockers (ARBs) are now available. The AT(1) receptor is a member of the G protein-coupled receptor (GPCR) superfamily and block the diverse effects of Ang II. Several ARBs are available for clinical use. Most ARBs have common molecular structures (biphenyl-tetrazol and imidazole groups) and it is clear that ARBs have 'class effects'. On the other hand, recent clinical studies have demonstrated that not all ARBs have the same effects, and some benefits conferred by ARBs may not be class effects, and instead may be 'molecular effects'. In addition, each ARB has been clearly shown to have specific molecular effects in basic experimental studies, and these effects may be due to small differences in the molecular structure of each ARB. However, it is controversial whether ARBs have molecular effects in a clinical setting. Although the presence of molecular effects for each ARB based on experimental studies may not directly influence the clinical outcome, this possibility has not been adequately evaluated. This review focuses on the class effects versus molecular effects of ARBs from bench to bedside.
The renin-angiotensin system (RAS) is intricately involved in cardiovascular homeostasis. It is well known that angiotensin II, the key effector in RAS, contributes to a range of cardiovascular pathologies and diseases via angiotensin II type-1 receptor (AT1R) activation. However, the role of angiotensin II type-2 receptor (AT2R) regulation is less well understood. Recent studies describe the role of the AT2R on cardiovascular function in normal and pathologic conditions. The data describe an important role of AT2R in blood pressure regulation, cardiac hypertrophy and fibrosis, myocardial infarction and vascular homeostasis.
Knowledge of the relationship between protein's structure and its dynamic behavior is essential for understanding protein function. In this study, the description of a protein three-dimensional structure as a network of hydrogen bonding interactions (HB plot) is introduced as a tool for exploring protein structure and function. HB plot offers a simple way of analyzing protein secondary and tertiary structure. Moreover, hydrogen bonds stabilizing secondary structural elements and those formed between distant amino residues--defined as tertiary hydrogen bonds--can be easily distinguished in HB plot, thus, amino acid residues involved in stabilizing protein structure and function can be easily identified. By analyzing the network of tertiary interactions the possible spread of information within a protein can be investigated as well. The alteration in tertiary hydrogen bonding network during conformational transitions were investigated through case studies; and showed the applicability of HB plot in exploring mechanistic details in proteins.
Over the past ten years, in vitro experimental tools to characterize ADME-Tox profiles of compounds have been applied in early stages of the drug discovery process to increase the success rate of discovery programmes and to progress better candidates into drug development. Application of in silico ADME-Tox models has further enhanced discovery support, enabling virtual screening of compounds and thus, application of ADME-Tox at every stage of the discovery process. Ultimately, effective and efficient ADME-Tox support of discovery will depend on a complementary and synergistic use of experimental and in silico ADME-Tox.