A theoretical model to study the interactions of xanthene-1,2,3-triazolyl- N-riboside and xanthene-piperidinyl-benzisoxazole based conjugates with the insulin: Design, docking and ADME studies

Literature reported the insulin is an important for the humans and it is secreted in the pancreas and controls, regulates the glucose level. It also controls the mechanism and growth. On decreasing the amount of insulin can caused diabetes, several cancers and other disease. Therefore, there is a need to find promising candidates can binds with insulin and stabilize them. Organic compounds containing hetero atoms have lots of biological potency in different area, therefore, researchers are designing new biological potent compounds. Further, insilico studies attracted the researchers in last one decade mainly to get the drug in less time with a clear strategy. In the present work, authors have designed two types of conjugates, xanthenes with trizole as well benzisoxazole and study their interaction with the insulin using computational methods. The library of compounds was screened through molecules docking in terms of binding energy between the designed compound and the active site of the receptor. Further, their ADME properties are investigated. CMPD19 showed best binding affinity with the insulin and may be considered as oral drug based on the bioactive scores.


Introduction
Insulin hormone which is the major secretion of the β-cells of endocrine gland (pancreas), regulates the extent of glucose in blood by promoting glucose uptake or by quashing glucose production. Diabetes mellitus (DM) is a result of the failure of insulin making or malfunction of tissue sensitivity to insulin [1][2][3][4][5][6][7][8][9]. Type 1 diabetes mellitus (T1DM) is caused due to the loss of β-cells of pancreas through immune destruction, which leads to inadequate insulin production. Hence, the T1DM patients needed to give insulin from outside for maintaining the required glucose level in the blood [10][11][12][13]. The declined tissue sensitivity towards insulin hormone leads to type 2 diabetes mellitus (T2DM). In order to cure T2DM, the hepatic glucose production is reduced and the peripheral glucose utilization is boosted by working on two different approaches, one is to enhance the release of insulin and the other is to improve the action of insulin [14,15]. Nevertheless, these treatment methods no longer remains very effective when the disease progresses on advance stages and type 2 diabetic patients requires insulin therapy. Therefore, to identify new molecular targets for the development of novel remedial approaches to restore insulin action always be a matter of good research.
Keeping in mind the bio-mimicry i.e. bio-motivated design and rational design two or more different biologically active molecules could be joined in a single molecular entity to obtain the hybrid molecules with two distinct pharmacophores and dual mode of action. Hence the technique of molecular hybridization is used in drug design and discovery to get the molecules having improved biological activity with the same or different mode of action compared to the precursors [30,31]. Computational approaches could also be valuable tool to take decision for the synthesis of molecules to make libraries of desired compounds. Herein, the authors have designed two schemes to get conjugates of xanthenes with the trizole and benzisoxazole. Further, the screening of the compounds was done using the docking and ADME properties to get a promising candidate.

Experimental
Designing of biological potent xanthenes based conjugates to study the interaction with the insulin as in Scheme 1 and 2. Authors have designed the synthesis of xanthene-1,2,3-Triazolyl-N-riboside via the reaction between the sugar or the 2-azido-5-

Molecular docking
All the compounds designed are drawn using Chemdraw and then they were optimized using MM2 for the study. Protein data bank file for the insulin is taken from the RCSB and the ID is 5mam. Then, the pdb is prepared for the docking by the removal of the ligands/ cofactors/ solvents and then addition of atoms, if any. The interactions between the insulin and the designed compounds was performed using molecular docking with the help of a computational tool i.e. iGemdock. The screening is done based on the binding energy for the formation of the complex between the compound and the insulin. This binding is obtained by the electrostatic and van der Waals interaction along with the hydrogen bonding. Further, the molecular interactions of best five compounds with insulin at residues level were studied [32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47].

Absorption, distribution, metabolism, and excretion (ADME) properties of the designed compounds
Absorption, distribution, metabolism, and excretion (ADME) properties of the compounds were determined using http://www.swissadme.ch/, an online web-server. It is used to explain the disposition of a molecule in the organism. These properties of a molecule affect the tissues in the organisms and explain the pharmacology of the molecule.

Conclusion
Insulin is used to control the mechanism and growth in humans. With decrease in amount of the insulin may cause diabetes and some other diseases. Therefore, there is a need to explore to find the promising molecules for the binding with insulin. A library of the conjugates based on the xanthenes with ribose and benzisoxazole are designed studied their interaction with insulin using molecular docking and ADME properties. Based on the molecular docking, it showed the best binding affinity with insulin. Further, based on the ADME scores, CMPD19 may be a promising candidate.