The aim of this study is to perform molecular docking studies to identify potential binding affinities of the phyto-compounds from compounds claulamines E, clausemarin B, Clausenaline C, Clausenaline E, Murrayanine, vanillic acid, Xanthotoxol for searching of lead molecule for anti-diabetic activity. 
Computer assisted drug design approach has contributed to successfully disclosure of against diabetic agent. Molecular docking keeps on being a great promise in the field of computer based drug design.
The procedure of molecular docking includes investigation of various holding methods of one ligand with targeted receptors protein. We have found that numerous values of Molecular docking score by Schrodinger. Compounds claulamines E, clausemarin B, Clausenaline C, Clausenaline E, Murrayanine, vanillic acid, Xanthotoxol respectively. Among all the compounds Clausenaline E showed the best docking score. So from this investigation we can say that this compound Clausenaline E can be suggested for further experiment for the grater pharmacological effect in diabetic patient.

• Piper-sylvaticum

• Molecular docking

• Thrombolytic activity

Nihar SW, Hoque Tanim MA, Siddique TI, Hoque A, Sultana S, et al. (2018) In silico Docking Studies of Some Isolated Compounds of Clausena Lansium (Lou.) Against Diabetic Activity. J Pharmacol Clin Toxicol 6(1):1100.

In South Asian countries diabetes has become the seventh leading attributable risk factor [1,2]. By 2035 the number of affected people is expected to increase to 592 million globally [3]. About 80% of adults suffer in diabetes in low- and middle-income countries [4]. Diabetes is a serious complex condition which can affect the entire body. Blood glucose is the main source of energy and comes from the food we eat. Diabetes is a disease that occurs when blood glucose is too high. Insulin, a hormone is prroduced by the pancreas which enables glucose from food to get into our cells to be used for energy. Therefore, there has been a developing interest to analyze the antidiabetic properties of plants. A large number of plants and plant-parts have been investigated for their beneficial role and anti-diabetic properties [5,6].

Clausena lansium (Lou.) has a place with the family Rutaceae and is started from Southern China and discovered likewise in Bangladesh, India and so forth. The mash can be utilized to plan organic product mugs, sweets, stick, or jam. What’s more, the matured natural product can be utilized to plan carbonated refreshments like champagne, albeit dried Clausena lansium is a more attractive product. Previous investigations of bioactivities, especially the concentrates of its leaf and seed, for the most part centered around the hepatoprotective, antiplatelet, hypoglycemic, antifungal and antiviral activities. In any case, no methodical investigation has been directed on the Clausena lansium peel despite the fact that it is utilized as a people medication in China for the treatment of stomachic, and bronchitis and additionally it goes about as a vermifuge. Out of the blue, this examination researched the cancer prevention agent and anticancer exercises of the Clausena lansium peel removes and showed the strong bioactivities of the concentrates appropriate to be utilized as characteristic cell reinforcement mixes or pharmaceutical supplements [7-11].

Molecular docking is a key apparatus in computer-assisted drug design and development. Docking has been used to perform virtual screening on extensive libraries of compounds and propose basic theories of how the ligands bind with the target with lead optimization. Another potential use of docking is optimization stages of the drug-discovery cycle.

Protein preparation

3D crystal structure of Pancreatic Alpha-Amylase With A Carbohydrate Inhibitor is downloaded from Protein Data Bank [12]. By using the Protein Preparation Wizard of SchrödingerMaestro v 10.1 the structure was prepared and refined. Charges and bond orders were assigned, hydrogens are added to the heavy atoms, were converted to methionines, and all waters were deleted. By Using force field OPLS_2005 minimization was carried out setting maximum heavy atom RMSD to 0.30 Å.

Preparation of ligand

Compounds were retrieved from Pubchem databases, i.e claulamines E, clausemarin B, Clausenaline C, Clausenaline E, Murrayanine, vanillic acid, Xanthotoxol. The 2D structures for these were built by using Schrödinger-Maestro v 10.1.

Receptor grid generation

Receptor grids were calculated for prepared proteins such that various ligand poses bind within the predicted active site during docking.Grids were generated keeping the default parameters of van der Waals scaling factor 1.00 and charge cutoff 0.25 subjected to OPLS 2005 force field in glide. A cubic box of specific dimensions centred around the centroid of the active site residues (Reference ligand active site) was generated for receptor. For docking experiments, The bounding box was set to 14 × 14 × 14.

Glide standard precision (SP) ligand docking

SP flexible ligand docking was carried out in Glide of Schrödinger-Maestro v10.1 [13,14], within which penalties were applied to non-cis/trans amide bonds. Van der Waals scaling factor and partial charge cutoff was selected to be 0.80 and 0.15, respectively for ligand atoms. Final scoring was performed on energy-minimized poses and displayed as Glide score. The lowest Glide score value was recorded for each ligand as the best docked pose

In order to study the interaction of the compounds claulamines E, clausemarin B, Clausenaline C, Clausenaline E, Murrayanine, vanillic acid, Xanthotoxol with 1PPI, we performed Glide docking analysis by Schrodinger suite v 10.1, where among of these compounds Clausenaline E shows highest docking score -5.467 shown in Table 1.

Table 1: Docking analysis of claulamines E, clausemarin B, Clausenaline C, Clausenaline E, Murrayanine, vanillic acid, Xanthotoxol with 1PPI.

The negative and low value of Piperine glide energy of binding demonstrates a strongly favorable bond between 1PPI and in most favorable conformations. The results of docking analysis was described in Table 1 and Figure 1.

Figure 1 Docking results of Piperine, Piperlonguminine, β-sitosterol and N-isobutyl deca-trans-2-trans-4-dienamide with tissue plasminogen activator (PDB: 1A5H).

Since there is no cure for diabetes yet there are approaches to bring down the dangers. Despite the fact that diabetes is confusion, it can likewise prompt different factors, for example, heart assault, kidney disappointment, or passing. A man with diabetes needs to keep up a sound way of life including eating the correct nourishment, working out, controlling their glucose level, and be hopeful [15-19].

Diabetes happens in a few structures however the real ones are Type I and I. Our computer aided drug-design has successfully discovered the source of several anti-diabetic agents. We tried to find out the maximum effect of compound which may give better therapeutic effect for diabetes with fewer side effects. From the above table we can determine the compound Clausenaline E shows the greatest binding affinity for the targeted receptor. And the docking score Clausenaline E glide emodel and glide energy shows that the particular compound Clausenaline E can give the better therapeutic effect than others.

From overall study we can estimate that the compound can be suggested for further in vivo experiments. If we go through all data and studies it shows how it clearly indicated that Clausenaline E can be utilized to care for diabetes. Our investigations may lay the base of further investigation of the - for its ant diabetic potential. The above discoveries additionally approve the ethno pharmacological information on this plant. Thus, it can be inferred that has high potential as ant diabetic particularly against pathway in diabetes.

The authors thank GUSTO A Research Group for providing the the financial support and software.

1. Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2013; 380: 2224-2260.

2. Rahman MS, Akter S, Abe SK, Islam MR, Mondal MN, Rahman JA, et al. Awareness, treatment, and control of diabetes in Bangladesh: a nationwide population-based study. PloS One. 2015; 10: e0118365.

3. Guariguata L,Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract. 2014; 103: 137-149.

4. Federation ID. IDF diabetes atlas. Brussels: International Diabetes Federation. 2013.

5. Yeo J, Kang YM, Cho SI, Jung MH. Effects of a multi-herbal extract on type 2 diabetes. Chin Med. 2011; 6: 10.

6. Kumar S, Saini M, Kumar V, Prakash O, Arya R, Rana M, et al. Traditional medicinal plants curing diabetes: A promise for today and tomorrow. Asian J Traditional Med. 2012; 7: 178-188.

7. Malmberg A, Yaksh T. Hyperalgesia mediated by spinal glutamate or substance P receptor blocked by spinal cyclooxygenase inhibition. Science. 1992; 1276-1279.

8. Liu GT, Li WX, Chen YY, Wei HL. Hepatoprotective action of nine constituents isolated from the leaves of Clausena lansium in mice. Drug Dev Res. 1996; 39: 174-178.

9. Fan GJ, Han BH, Kang YH, Park MK. Evaluation of inhibitory potentials of chinese medicinal plants on platelet-activating factor (PAF) receptor binding. Natural Product Sciences. 2001; 7: 33-37.

10. Morton JF. Fruits of warm climates. 1987.

11. Shen Z. The hypoglycemic effect of clausenacoumarine. Yao xue xue bao= Acta pharmaceutica Sinica, 1989; 24: 391-392.

12. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat N, Weissig H, et al. The Protein Data Bank, 1999-, in International Tables for Crystallography Volume F: Crystallography of biological macromolecules. Springer. 2006; 675-684.

13. Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, et al. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem. 2004; 47: 1739-1749.

14. Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, et al. Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein− ligand complexes. J Med Chem. 2006; 49: 6177-6196.

15. Anjana R, Pradeepa R, Deepa M, Datta M, Sudha V, Unnikrishnan R, et al. Prevalence of diabetes and prediabetes (impaired fasting glucose and/or impaired glucose tolerance) in urban and rural India: Phase I results of the Indian Council of Medical Research–India Diabetes (ICMR–INDIAB) study. Diabetologia. 2011; 54: 3022-3027.

16. Kaushik P, Kokhra SL, Rana AC, Kaushik D. Pharmacophore modeling and molecular docking studies on Pinus roxburghii as a target for diabetes mellitus. Adv Bioinformatics. 2014.

17. Tota K, Rayabarapu N, Moosa S, Talla V, Bhyravbhatla B, Rao S. InDiaMed: a comprehensive database of Indian medicinal plants for diabetes. Bioinformation. 2013; 9: 378.

18. Marles RJ, Farnsworth NR. Antidiabetic plants and their active constituents. Phytomedicine. 1995; 2: 137-189.

19. Kaushik P, Kaushik D, Khokra SL. Ethnobotany and phytopharmacology of Pinus roxburghii Sargent: a plant review. J Integr Med. 2013; 11: 371-376.