Docking study on 2-cyanopyrrolidide-pyrrolidinyl as Dipeptidyl peptidase IV inhibitors as antidiabetic agents
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1 Docking study on 2-cyanopyrrolidide-pyrrolidinyl as Dipeptidyl peptidase IV inhibitors as antidiabetic agents *Vikram Choudhary, K. L. Seervi, Shaurya Pratap, R. S. Bhadauria Department of Pharmaceutical Chemistry, Shrinathji Institute of Pharmacy, Upali Oden, Nathdwara, Rajsamand , Rajasthan, India Received on 10/02/2018 Revised on 22/02/2018 Accepted on 28/03/2018 ABSTRACT Dipeptidyl peptidase IV (DPP IV) inhibition has been considered as an attractive target for the development of novel antidiabetic agents. Highly potent DPP IV inhibitors have been discovered with the help of docking study. In the light of above facts, docking study was performed on thirty eight 2-cyanopyrrolidide-pyrrolidinyl derivatives as DPP IV inhibitors. The DPP-IV protein structure was retrieved from the RCSB Protein Data Bank (PDB entry code: 3W2T). The binding mode between these derivatives and active site of DPP IV enzyme was established by Sybyl X The docking study revealed that hydrogen bonding interaction of these derivatives have been developed with Arg125, Gln553 and His740 amino acid residues of DPP IV enzyme. The unbounded Arg125 is essential for the survival of DPP IV enzyme. The CN of ring A, NH 2 ofring B and CN of ring C of most active derivative developed hydrogen bond interaction with Arg125, His740 and Gln553, respectively and this hold true for most of derivatives of the series. The results are promising and can be used to design novel DPP IV inhibitors. Key Words : Dipeptidyl peptidase, antidiabetic agents, Docking, 2-cyanopyrrolidide-pyrrolidinyl, Dipeptidyl peptidase IV *Corresponding author: Mr. Vikram Choudhary Department of Pharmaceutical Chemistry Shrinathji Institute of Pharmacy Upali Oden Nathdwara Dist. Rajsamand, Rajasthan, India Choudharyvickyinc@gmail.com Phone No. :
2 Introduction: Molecular Docking : Molecular Docking is a key tool in structural molecular biology and computer assisted drug design. The goal of ligand- protein docking is to predict the predominant binding mode(s) of a ligands with a protein of known three dimension structure. Types of Molecular Docking Lock and Key\Rigid Docking In rigid docking, both the internal geometry of the receptor and ligand is kept fixed and docking is performed. Induced fit\flexible Docking - An enumeration on the rotations of one of the molecules (usually smaller one) are performed. Type 2 diabetes mellitus (T2DM) occurs due to decrease in the sensitivity of β cell in pancreas as well as insulin secretion and metabolism. T2DM is a metabolic disorder characterized by insulin resistance, hyperglycemia, hyperlipidemia, surplus glucagon secretion and insufficient secretion of the incretin hormone glucagonlike peptide-1 (GLP-1). Untreated type 2 can cause numerous chronic complications such as retinopathy, nephropathy, neuropathy, and cardiovascular diseases, the latter leading to increased mortality. Several enzymes disturb the insulin activity in which most common is dipeptidyl peptidase IV (DPP IV), activated at the time of meal intake. Thus DPP IV is a clinically validated target for the treatment of T2DM [1,2] and has received considerable interest from the pharmaceutical industry in last few years. The models resulting from the docking study provided some beneficial clues in structural modification of these inhibitors, for further designing DPP IV inhibitors. DPP -4 Inhibitors for Treatment of Type 2 Diabetes DPP -4 Inhibitors Inhibit DPP 4, an enzyme that degrades incretin hormones including GLP-1 and GIP. Enhance insulin secretion in a glucose dependent manner. Suppress elevated glucagon secretion in a glucosedependent manner. Benefits Weight neutral. Low risk of hypoglycemia. Side Effect Upper respiratory tract infection. No significant GI side effects. Possible acute pancreatitis. Mechanism of action of DPP4 Inhibitors Several enzymes disturb the insulin activity in which most common is dipeptidyl peptidase IV (DPP IV), activated at the time of meal intake. The models resulting from the docking study provided some beneficial clues in structural modification of these inhibitors, for further designing DPP IV inhibitors. Objective Commercially available anti-diabetic drugs are effective and widely used for the treatment of diabetic conditions but long term treatment is limited due to their side effects such as lactoacidosis, hepatic toxicities, cancer, weight gain and oedema. The sitagliptin chemically posses important amino keto and heterocyclic ring which binds with DPP IV enzyme and inhibits its activity. Long term Commercially available anti-diabetic drugs are effective treatment but is limited due to their side effects such as lactoacidosis, hepatic toxicities, cancer, weight gain and oedema. To overcome the failures of monotherapy and to address the different underlying defects of the pathology of T2DM, herbal drugs are effectively being used, either singly or in combination, as adjuncts to dietary therapeutic measures. To re-design and optimization of existing antidiabetic agents extends their lifetime as useful drugs, there is also a need to identify novel chemical scaffolds that inhibit existing and previously unexploited biological targets. To have promising anti-diabetic activity with minimum side effects. In the proposed work computer aided structure based drug design technique will be used to design and develop some DPP IV inhibitors
3 To overcome the failures of mono therapy and to address the different underlying defects of the pathology of T2DM, herbal drugs are effectively being used, either singly or in combination, as adjuncts to dietary therapeutic measures. Although the redesign and optimization of existing antidiabetic agents extends their lifetime as useful drugs, there is also a need to identify novel chemical scaffolds that inhibit existing and previously unexploited biological targets. Material And Methods The total thirty eight molecule of DPP IV inhibitory activity were selected for molecular modeling analysis. The chemical structures were constructed on the sketch module of Sybyl X2.0 software. The molecular modeling studies require the minimization of structure, calculation of the force field and charges. The energy minimization and charge calculation done by Tripos force field and Pullman charge (or other) respectively. The DPP-IV protein structure was retrieved from the RCSB Protein Data Bank (PDB entry code: 3W2T). The DPP-IV protein structure was utilized in docking, all ligands and water molecules were removed, polar hydrogen atoms, AMBER7FF99 charges were added and
4 energy minimization executed. The Surflex-Dock module used to dock ligands into a ligand-protein s extracted (vildagliptin) binding site generated protomol to analyze molecular docking. The protomol bloat value was set as 1 and the protomol threshold value as 0.5 to obtained meaningful binding pocket. Other parameters are established by default in software. PDB Description Retrieved from the RCSB Protein Data Bank (PDB entry code: 3W2T). 3W2T: Crystal structure of human depiptidyl peptidase IV (DPP-4) in complex with vildagliptin Chemical Name of Ligand : (2S)-1-{N-[(1R,3S,5R,7S)- 3-hydroxytricyclo[ ~3,7~]dec- 1- yl]glycyl}pyrrolidine-2-carbonitrile Name of Ligand : Vildagliptin Chemical Formula of Ligand : C 17 H 25 N 3 O 2 Chemical Structure of Ligand (Vildagliptin ) Result And Discussion Docking analysis explore the binding affinity between these pyrrolidinyl derivatives and the DPP-IV protein inhibitor vildagliptin (protomol), to recognize the suitability of model. We selected the most potent compound 35 in the docking experiment to perform the deeper docking analysis and discussion below Figure 1. In order to get a better understanding of the variations in biological activities, we compared the binding modes of each group seeking to explore their similarities and differences. Our docked models revealed that hydrogen bonding is an important interaction between the inhibitor and the target receptor pdb 3W2T. According to the docking study, a total of three hydrogen bond interactions of 35 were as Arg125, Gln553 and His740 with 3W2T. Interestingly, the common structure of cis-3-amino-4-(2-cyanopyrrolidide)-pyrrolidinyl derivatives.the hydrogen bonds are shown by yellow color broken lines. The CN of ring A, NH 2 ofring B and CN of ring C of most active derivative developed hydrogen bond interaction with Arg125, His740 and Gln553, respectively and this hold true for most of derivatives of the series.the results are promising and can be used to design novel DPP IV inhibitors. Thus, by employing the given knowledge regarding various fields interaction, more potent inhibitors can be designed and synthesized for analysis of their anti-diabetic activity followed by their further development as novel antidiabetic drugs. We selected the most potent compound 35 in the docking experiment to perform the deeper docking analysis and discussion below Figure
5 CH 3 CN O NH 2 CN B C A N H CH 3 Most Active Compound Figure 1: Stereoview of the docked conformations of most active inhibitor 35, in the active site of DPP IV enzyme, important amino acid residues which form interaction with compound were Arg125, Gln553 and His740 with 3W2T
6 Docking Analysis Fig 2 Docking pose of all compounds. Fig 3 Docking pose of most active compound
7 Docking interactions S. No. Compound id/ standard Amino acid interactions Arg125 Gln553 His740 Mol dock score (kcal/mol) 1. Compound Compound Compound Our docked models revealed that hydrogen bonding is an important interaction between the inhibitor and the target receptor pdb 3W2T. According to the docking study, a total of three hydrogen bond interactions of 35 were as Arg125, Gln553 and His740 with 3W2T. Thus, by employing the given knowledge regarding various fields interaction, more potent inhibitors can be designed and synthesized for analysis of their anti-diabetic activity followed by their further development as novel antidiabetic drugs Conclusion Dipeptidyl peptidase IV (DPP IV) inhibition has been considered as an attractive target for the development of novel antidiabetic agents. Highly potent DPP IV inhibitors have been discovered with the help of docking study. In the light of above facts, docking study was performed on thirty eight 2-cyanopyrrolididepyrrolidinyl derivatives as DPP IV inhibitors. The DPP-IV protein structure was retrieved from the RCSB Protein Data Bank (PDB entry code: 3W2T). The binding mode between these derivatives and active site of DPP IV enzyme was established by Sybyl X 2.0 software. The docking study revealed that hydrogen bonding interaction of these derivatives have been developed with Arg125, Gln553 and His740 amino acid residues of DPP IV enzyme. The unbounded Arg125 is essential for the survival of DPP IV enzyme. Acknowledgment It is with a profound sense of gratitude; I owe my first and foremost indebtedness to Dr. Rajesh Sharma (Prof. and Head), School of Pharmacy, Devi Ahilya Vishwavidyalaya, Indore &Dr. R. S. Bhadauria (Principal & Head), Shrinathji Institute of Pharmacy, Nathdwara for providing needful support to carry out this work. References 1. R.D. Cramer, J.D. Bunce, D.E. Patterson, and I.E. Frank, Crossvalidation, bootstrapping, and partial least squares compared with multiple regression in conventional QSAR studies, Quant. Struct. Act. Relat. 7 (2006), pp Abdullah A, Peeters A, Courten M, Stoelwinder J. The magnitude of association between overweight and obesity and the risk of diabetes: a meta-analysis of prospective cohort studies. Diabetes research and clinical practice.89 (2010), Shrikanth H, Havale, Manojit P. Medicinal chemistry approaches to the inhibition of dipeptidyl peptidase-4 for the treatment of type 2 diabetes. Bioorganic & Medicinal Chemistry 17 (2009),
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