Vol 12, Issue 9, 2019 Online - 2455-3891 Print - 0974-2441 IN SILICO ANALYSIS OF ACTIVE CONSTITUENTS OF SILYMARIN AS ΑLPHA-GLUCOSIDASE ENZYME INHIBITORS IN TYPE 2 DIABETES MELLITUS AHMAD ZONOUBI 1 *, PRASHANTHA CN 2 , D VISAGA PERUMAL 1 , ZAHRA MAFIBANIASADI 3 1 Department of Pharmaceutical Chemistry, T. John College of Pharmacy, Bengaluru, Karnataka, India. 2 Department of Biotechnology, School of Applied Sciences, REVA University, Bengaluru, Karnataka, India. 3 Department of Pharmaceutics, T. John College of Pharmacy, Bengaluru, Karnataka, India. Email: ahmad.zonoubi84@gmail.com Received: 05 June 2019, Revised and Accepted: 25 July 2019 ABSTRACT Objective: Type 2 diabetes mellitus (T2DM) is an acute metabolic disorder, in which the vogue is increasing persistently globally. The maltase-glucoamylase/alpha-glucosidase inhibitor is an oral antidiabetic drug collectively, which is utilizing for regulating carbohydrates that ordinarily transformed into simple sugars and absorbed by the intestine. Researchers need to constantly explore alternative therapeutic strategies for the clinical management of DM due to the increased adverse event caused by conservative antidiabetic agents. The present study proposes a substitute drug to examine the seven bioactive phytocomponents of Silybum marianum (milk thistle) that can regulate the hyperglycemia by downregulating alpha-glucosidase and its activity. Methods: Different integrated web-based in silico tools and techniques were used to model the enzyme (receptor) as well as to determine the druggability of different active constituents of silymarin and their pharmacokinetics were predicted. Further, the active site of the enzyme was predicted followed by molecular docking method. Results: The results show silychristin A and silydianin having less carcinogenicity and strong interaction to the target protein (alpha-glucosidase) compare to the reference drugs (acarbose and miglitol) and these two molecules can be used for the best drug molecules in T2DM. Conclusion: In the proposed study, the in silico analysis helps researchers to utilize these compounds for clinical applications. The conclusion also suggests that synthetically and semi-synthetically, nucleus and peripheral modifications, either in the form of skeletal rearrangements or partial degradations as well as functional group addition and replacement of the active molecules present in silymarin giving access to new structural motifs, which can be used in future as a lead compounds for antagonising the alpha-glucosidase in the treatment of diabetes mellitus. Keywords: Type 2 diabetes mellitus, Alpha-glucosidase, Silymarin, Silychristin A, Silydianin, Acarbose, Miglitol, Molecular docking, Milk thistle. INTRODUCTION Diabetes mellitus (DM) is undoubtedly one of the human’s oldest known diseases. It was first reported about 3000 years ago in the Egyptian manuscript [1]. A perfect variance among T1 and Type 2 DM (T2DM) was undoubtedly defined [2,3]. T2DM was previously illustrated in 1988 as a component of metabolic syndrome [4]. The prompts of T2DM are complex, multifaceted and comprise both genetic and environmental features as well as behavioral risk factors that affect beta-cell obligation and tissue insulin sensitivity [5-7]. Persons with T2DM are more susceptible to various forms of short-term and long-term medical difficulties, which occasionally lead to premature death. This has been seen in patients with T2DM mostly due to the pervasiveness of this type of DM. As the prevalence of this metabolic disorder, it is promptly rising and standard treatment refuses to steady the disease in most patients, prevention would be perceived as a key objective in the relatively proximate future. Persons who experience T2DM go through a phase of impaired glucose tolerance (IGT). Defects in the action or even secretion of insulin seem to be the two main complications ultimately leading to the development of glucose intolerance. Any interference in the phase of IGT that decreases insulin resistance protects beta-cells or both should also prevent or delay progression to diabetes. Several potential drugs such as sulfonylureas, meglitinides, biguanides, and thiazolidinediones and alpha-glucosidase inhibitors can be used in medical treatments to regulate high blood glucose problems (hyperglycemia). In general, alpha-glucosidase is concomitant through the breakdown of polysaccharide and disaccharides into monosaccharide glucose [8,9]. Alpha-glucosidase inhibitors are oral antidiabetic medications which administered to alter the breakdown of carbohydrates that are transformed into simple sugars and absorbed by the intestines [10]. Alpha-glucosidase inhibitors appear to have a greater affinity of 10,000–100,000 times with carbohydrate-binding sites than oligosaccharides and polysaccharides. Oligosaccharides and polysaccharides cannot be converted into simple sugars that the body can absorb by inhibition of alpha-glucosidase enzyme [11]. Hereafter, alpha- glucosidase inhibitors are crucial medications to prevent the absorption of carbohydrates in the intestine and can be used to treat T2DM and IGT [12]. Thus, these hypoglycemic agents are applied to patients with early diabetes or combined with other drugs [13]. Medicinal plants and herbs are noticeable in traditional medicine and have appealing pharmacological activities [14] and the most significant properties of medicinal plants are, either they show lower side effects or they are without any side effects.. During the past decade, alpha-glucosidase inhibitors from natural resources have been extensively established as highly purposeful foods or lead compounds to modulate diabetes. Recently, drug designs used to significantly diminish blood glucose levels and try to maintain blood glucose homeostasis with slightly fewer adverse effects. In the structure-based drug design method, structures of considered target proteins are usually utilizing to perceive novel compounds that are therapeutically applicable. Computational or molecular docking is a simulation strategy that predicts molecules that properly bind to targets including enzymes and receptor proteins. Moreover, the rational methodology in virtual screening is known as the hierarchical method, which seems to be a valuable tool for computing © 2019 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4. 0/) DOI: http://dx.doi.org/10.22159/ajpcr.2019.v12i9.34460 Research Article