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Exploring Anti-Hyperglycemic Potential of Alkaloid Compounds from Catharanthus Roseus G

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Exploring Anti-Hyperglycemic Potential of Alkaloid Compounds from Catharanthus Roseus G WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES Ly et al. World Journal of Pharmacy and Pharmaceutical Sciences SJIF Impact Factor 6.647 Volume 6, Issue 8, 82-110 Research Article ISSN 2278 – 4357 EXPLORING ANTI-HYPERGLYCEMIC POTENTIAL OF ALKALOID COMPOUNDS FROM CATHARANTHUS ROSEUS G. DON (L) AGAINST VARIOUS TYPE II DIABETES TARGETS BY IN SILICO VIRTUAL SCREENING Thanh-Hoang Nguyen-Vo1,2, Dat Nguyen1, Phuc H. Le1 and Ly Le1* 1School of Biotechnology, International University - VNU, HCMC, Vietnam. 2Institute for Computational Science, Ton Duc Thang University, HCMC, Vietnam. GRAPHICAL ABSTRACT Article Received on 31 May 2017, Revised on 20 June 2017, Accepted on 11 July 2017 DOI: 10.20959/wjpps20178-9647 *Corresponding Author Ly Le School of Biotechnology, International University - VNU, HCMC, Vietnam. ABSTRACT Background: Catharanthus roseus (L.) G. Don (C. roseus) is a prominent anticancer herb having high alkaloid content. Besides known anticancer effect, this plant has been also traditionally used as an effective anti-diabetic treatment in many Asian countries, such as India, Malaysia, and Vietnam. Some in vivo and in vitro studies on its compounds and fractional extracts have confirmed its strong anti-hyperglycemia. This fact raises a question whether alkaloid compounds probably play any function in inhibitory activity on proteins related to Type 2 Diabetes Mellitus (T2DM). This study, therefore, was conducted not only to assess the role of alkaloid compounds in glucoregulatory pathway but also investigate other chemical groups treating T2DM besides known ones such as polyphenols and terpenoids. Objective: The study aims to calculate the binding affinity of alkaloids compounds of C. roseus toward four target proteins including 11β-HSD1, PTP1B, α-glucosidase and DPPIV www.wjpps.com Vol 6, Issue 8, 2017. 82 Ly et al. World Journal of Pharmacy and Pharmaceutical Sciences for anti-hyperglycemic effect and investigate their molecular interaction modes inside the protein’s active sites. Besides, pharmacokinetics of these compounds were also evaluate to support the conclusion of potent drug candidates for T2DM treatment. Method: Molecular Dynamics (MD) simulation was processed on pre-docking protein to assess the their stability. Then, the structure-based virtual screening was processed to evaluate the binding free energy of the alkaloid compounds when they were in contact with the protein active sites. Potent compounds whose binding free energy was greater than or equal to those of the control ligands were selected for pharmacophore analysis to investigate which functional residue got involve in the interaction. Besides, pharmacokinetics evaluation was done to assess the adverse drug interaction. All the in silico results were combined to explain and suggest potent compounds. Results: All structure of protein was simulated to assess the stability before processing structure-based virtual screening. After structure-based screening, 12 potential compounds were sellected. Then, pharmacokinetics of all compounds was evaluated. Enzyme CYP2C9 is considered to be the least targeted isoform while CYP2D6 is the most targeted one, followed by CYPA4. Structure-based pharmacophore features of these compounds were also analyzed to understand their molecular interaction modes and explain the differences in binding free energy. Conclusion: After combining all the in silico result, there were 8 compounds (com_05, com_07, com_16, com_26, com_27, com_28, com_46, and com_56) were suggested to be potent drug candidates for experimental confirmation. Besides, com_56 (Strictosidine lactam) and com_46 (Mitraphyllline) are considered to be two best top-hit ligands with extremely high docked score. These ligands, however, well targeted on 11-β- HSD1. Moreover, since 4 in 8 compounds well targeted on 11-β-HSD1, this protein is undoubtly confirmed as the most suitable receptor for in vitro testing. On the other hand, although com_21 (Alstonine) was temporarily rejected due to targeting on up to 3 three CYP enzyme, the potential role of this compound should be carefully re-assess because it is the only multi-target compounds toward to 4 proteins. KEYWORDS: C. roseus; alkaloid; structure-based virtual screening; pharmacophore; pharmacokinetics. MANUSCRIPT 1. INTRODUCTION As a highly severe endocrine disorder, Diabetes Mellitus (DM) has become one of leading concerns in global medical emergency besides cancers and other infectious diseases. www.wjpps.com Vol 6, Issue 8, 2017. 83 Ly et al. World Journal of Pharmacy and Pharmaceutical Sciences According to the official definition of International Diabetes Federation (IDF), DM refers to a chronic condition in which body is unable to produce the sufficient amount of insulin (T1DM) or effectively utilize insulin (T2DM).[1] This study focused on T2DM, which is the most commonly seen case all over the world.[1] For many years, a lot of anti-diabetic drugs have been ceaselessly developed to solve the existing issues caused by current conventional drugs. Most of the conventional drugs, which are mainly produced by chemically synthetic processing, have been reported to result in unexpected adverse effects such as sulfonylureas, biguanides and thiazolidinediones.[2] Besides, the cost for T2DM treatment is extremely high and continually grows every year. The total U.S national cost of diagnosed diabetes in 2012 was reported to be about $245 billion, increased up by 41% compared to this number in 2007, which was only about $174 billion.[3] In fact, since T2DM treatments are usually elongated for a long time or even for whole life, searching for novel alternative treatment to lower cost and limit adverse effects is essential. In recent years, herbal remedies, originating from natural sources, have become preferable due to its fewer side effects and lower prices compared to the conventional ones. Furthermore, they are also able to target multiple mechanisms comprising of improvement in insulin sensitivity, stimulation of insulin secretion, or limitation of carbohydrate absorption.[4-6] According to VietHerb Ontology database, Catharanthus roseus (L.) G. Don (C. roseus), a herbaceous plant of family Apocynaceae, widely distributes all over the world, primarily tropical regions. C. roseus is a small medicinal plant of about 30 to 100 centimeters in height with glossy green leaves, rounded apex, fragrant-smelled flowers, follicle hair and many seeds. Its flower color varies in a range of more than 100 colors from white to violet. Traditionally, C. roseus has been used as a medication for T2DM in many Asian countries such as India, Malaysia, and Vietnam. Recently, although the anti-hyperglycemic effect of its fractional extracts and phytochemicals was manifested through some scientific studies on various animal models[7–10], the research gap in medicinal chemistry of these published compounds has not been filled. On the other hand, despite being essential in cancer treatment, the role of alkaloid group in T2DM-target-inhibitory activity is usually ignored or unregarded. A lot of studies on T2DM drug discovery only evaluated anti-hyperglycemic of polyphenol or terpenoid compounds due to good interaction inside the active site of the T2DM targets. Besides, these groups also have antioxidant activity which can protect cells from attacking of reactive oxygen species, or free radicals and partially contribute to reducing the risk of triggering cancer.[11] However, a recent study on cancer-induced mice model has www.wjpps.com Vol 6, Issue 8, 2017. 84 Ly et al. World Journal of Pharmacy and Pharmaceutical Sciences concluded that some anti-diabetic drugs may help cancer spread in mice. For years, most of the researchers supposed that antioxidants could neutralize the free radicals even though there were mixed results after many clinical trials on cancer prevention. The result of Hongting Zheng’s research groups demonstrated that if cancer was already present, antioxidants might fuel its proliferation instead of inhibiting the cancerous growth. The common class of DPPIV-inhibitory drugs including saxagliptin, sitagliptin, and anti-neuropathic a-lipoic acid (ALA) were identified to help enhance the risk of metastasis of exist- ing tumors but not enhance tumor incidence.[12] This study was conducted not to make an attempt to disprove the positive impact of antioxidants but to draw a noticeable issue on applying medication for T2DM patients in an appropriate way because there are a lot of scientific evidence confirmed that cancer incidence is closely related to diabetes as well as its risk factors and treatment.[13] The main purpose of this study is to screen the C. roseus’s alkaloid compounds for the potential drug candidates treating T2DM. The binding free energy, molecular interaction mode and pharmacokinetics of those compounds were investigated though currently advanced approaches. These T2DM-related proteins, including 11-β-HSD1[14–17], PTP1B[18– 21], α-glucosidase[22–25], and DPPIV[26–28] were prevalently used as drug targets basing on the clear confirmation in their functions and roles in glucoregulatory pathways. MATERIALS AND METHODS Screening for druglike molecules with Lipinski Rule of Five Bioclipse[29,30] (Version 2.6.2) was used to filter the compound with Lipinski Rule of Five or Rule of Five (RO5). This rule was applied to assess druglikeness to predict whether a compound is likely to be a bioactive. This rule was figured out by Christopher A. Lipinski in 1997 after he had observed some common features of
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