Insilico Activity Prediction of Thiazolidinediones Derivatives

 

P. Navya krishna*, Mukesh Mohite T.

Dept. of Pharmaceutical Chemistry, Dr. D. Y. Patil College of Pharmacy, Akurdi, Pune, Maharashtra-411044

 

ABSTRACT:

Diabetes mellitus is a common form of metabolic disorder where level of blood glucose in the bloodstream raises high, because of deficiency of insulin and development of insulin resistance in diabetic individuals. Diabetic patients develop serious complication with the development of disease, such as obesity, risk of stroke and heart failure. Even with great advances in modern medicine and potentially effective therapeutic approaches, search for effective treatment for diabetes is still a big challenge. In our present study we selected Thiazolidinediones (TZDs) as ligand. It is also known as "glitazones," bind to PPARγ, a type of nuclear regulatory protein involved in transcription of genes regulating glucose and fat metabolism. These PPARs act on peroxysome proliferator responsive elements (PPRE).The PPREs influence insulin-sensitive genes, which enhance production of mRNAs of insulin-dependent enzymes. In our Present research work we have chosen Peroxisomal (S)-2-hydroxy acid oxidase (1al7), UDP-glucose-4-epimerase(1a9y) as targets to screen our proposed chemical structures for anti-biabetic activity. The molecules were docked to the above said targets and the energy values obtained are as follows using the docking software. Depending on the energy values we have chosen the best three drug analogs they are Compound 3b { -8.8},Compound 3e { -8.7}, Compound 3f  {-8.8}. We tried to improve the binding efficiency and steric compatibility. Several modifications were made to the probable functional groups which are interacting with receptor molecules. Analogs of this drug molecule were prepared using ACD-chem.-sketch and docking. The modified drugs is sketched using chem.-sketch were found to be better than the conventional drugs available.

 

 

 

 

INTRODUCTION:

 

 

1,3-thiazolidine-2,4-dione

 

Molecular Formula:            C₃H₃NO₂S

Formula Weight:                 117.12642

 

Thiazolidinediones and its Derivatives:

1) The synthesis of a series of novel dispiropyrrolidines has been accomplished by 1,3-dipolar cycloaddition reaction with 5-arylidene-1,3-thiazolidine-2,4-dione and 5-arylidene-4-thioxo-1,3-thiazolidine-2-one derivatives as dipolarophiles. The synthesized compounds were screened for their antidiabetic activity on male Wistar rats.

 

 

 

2) The synthesis of thiazolidinedione derivatives that were designed previously using 2D QSAR for antidiabetic activity. Thiazolidine-2,4-diones derivatives having carboxylic ester appendages at N-3 and 5-substituted benzylidene were studied and the syntheses of only four derivatives were performed that were predicted to have promising antidiabetic activities.

 

 

 

TARGETS:

1) (S)-2-hydroxy-acid oxidase:

In enzymology,a (S)2hydroxyacidoxidase (EC 1.1.3.15)isan enzyme that catalyzes the chemical reaction(S)-2-hydroxy acid + O₂ {\displaystyle \rightleftharpoons } 2-oxo acid + H₂O₂. Thus, the two substrates of this enzyme are (S)-2-hydroxy acid and O₂, whereas its two products are 2-oxo acid and H₂O₂.This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-OH group of donor with oxygen as acceptor. The systematic name of this enzyme class is (S)-2-hydroxy-acid:oxygen 2-oxidoreductase. Other names in common use include glycolate oxidase, hydroxy-acid oxidase A, hydroxy-acid oxidase B, glycolate oxidase, oxidase, L-2-hydroxy acid, hydroxyacid oxidase A, L-alpha-hydroxy acid oxidase, and L-2-hydroxy acid oxidase. This enzyme participates in glyoxylate and dicarboxylate metabolism. It employs one cofactor, FMN.

 

 

Figure 1:(a) Peroxisomal (S)-2-hydroxy-acid oxidase

Organism: Spinaciaoleracea

Code:1al7

 

2) UDP-glucose 4-epimerase:

The enzyme UDP-glucose 4-epimerase (EC 5.1.3.2), also known as UDP-galactose 4-epimerase or GALE, is a homodimeric epimerase found in bacterial, fungal, plant, and mammalian cells. This enzyme performs the final step inthe Leloir pathway of galactose metabolism, catalyzing the reversible conversion of UDP-galactose to UDP-glucose. GALE tightly binds nicotinamide adenine dinucleotide (NAD+), a co-factor required for catalytic activity. Additionally, human and some bacterial GALE isoforms reversibly catalyze the formation of UDP-N-acetylgalactosamine (UDP-GalNAc) from UDP-N-acetylglucosamine (UDP-GlcNAc) in the presence of NAD+, an initial step in glycoprotein or glycolipidsynthesis.

 

Figure 2 : (b) UDP-glucose 4-epimerase

Organism: Escherichia coli

Code:1a9y

 

CHALCONES:

Chalcone is an aromatic ketone that forms the central core for a variety of important biological compounds, which are known collectively as chalcones. They show antibacterial, antifungal, antitumor and anti-inflammatory properties. They are also intermediates in the biosynthesis of flavonoids, which are substances widespread in plants and with an array of biological activities. Chalcones are also intermediates in the Auwers synthesis of flavones. Chalcones can be prepared by an aldol condensation between a benzaldehyde and an acetophenone in the presence of sodium hydroxide as a catalyst. This reaction has been found to work in without any solvent at all - a solid-state reaction. The reaction between substituted benzaldehydes and acetophenones has been used to demonstrate green chemistry in undergraduate chemistry education. In a study investigating green chemistry synthesis, chalcones were also synthesized from the same starting materials in high temperature water (200 to 350 degree centigrade).

 

 

 

Michale Adducts thiazolidinedionechalcones:

Among all heterocyclic compounds, Michale AdductsThiazolidinedionechalcones are one of the most important heterocyclic structures exhibiting remarkable pharmacological activities because it is an essential constituent of all cells. Michael Adducts Thiazolidinedione chalcones is a six-membered heterocyclic ring containing two nitrogen atoms at position 1 and 14 of the 5 and 6 membered rings.

 

 

 

EXPERIMENTAL WORK:

Step: 1

Preparation of Chalcone:

Equimolar mixture of 1,3-thiazolidine-2,4-dioneand different substituted aldehydes dissolved in 15ml of ethanol and added 40% KOH and stirred the entire reaction mixture for 6 hrs. Then the mixture is kept for overnight at room temperature. Then pour the above mixture in crushed ice. Then acidified with HCl. The obtained chalcone was recrystallized from ethanol.

 

Step: 2

Preparation of Michael adducts:

NaOH-1.0M was add to the stirred solution of chalcones (2.08g,10mmol) at room temperature in DMF (10ml) and nitromethane (0.61g,10mmol) the resulting mixture was stirred until the reaction was complete (TLC).

 

Step: 3

Reduction and ring cyclization:

Then granular zinc (3.27g: 50mmol) was added to the mixture and was stirred at 80°C and conc.HCl (20ml) was added very slowly. The mixture was stirred at 80°C under the reducing conditions for about 90min, and then allowed to come room temperature.  Neutralized with Saturated aqueous NaHCO₃ (30ml) and extracted with diethyl ether (3×20ml), filtered and concentrated. The crude product was purified by silica gel chromatography.

 

 

 

 

 

 

MATERIALS AND METHODS:

Tools and Materials Used: - For our present study we used bioinformatics tools, biological database like PDB (protein data bank) and software like ACD chem. sketch, organic chemistry portal and molecule docking. ACD/chem. sketch is the powerful all-purpose chemical drawing and graphics package from ACD/labs developed to help chemist quickly and easily draw molecules, reactions, and schematic diagrams, calculate chemical properties and design professional reports and presentations. ACD chem. sketch can convert “SMILES” notations to structure and vice versa .PDB (protein data bank) is the single worldwide archive of structural data of biological macromolecules, established in Brookhaven national laboratories (BNL) in 1971. It contains structural information of the macromolecules determined by X-ray crystallographic, NMR methods ect. Docking allows the scientist to virtually screen a database of compounds and predict the strongest binders based on various scoring functions. It explores ways in which two molecules, such as drugs and an enzyme or receptor fit together and docks to each other well, like pieces of a three-dimensional zigzag puzzle. The molecules binding to a receptor, inhibit its function, and thus act as drug. The collection of drug analogs and receptor complexes was identified via docking and their relative stabilities were evaluated using molecular dynamics and their binding affinities, using free energy simulations. All the parameters used for molecule docking are selected by default.

 

Table 1: Substitutions of Michael adducts thiazolidinedione derivatives and Smiles File

 

Table 2: Drug like properties predicted from Molsoft, MolinspirationProperty calculator the following are the properties of Michael Adducts thiazolidinedionederivatives.

Sr.No	CODE	Mi logp	TPSA	n atoms	MW	N ON	n OHNH	n violations	nrotb	volume	Drug like liness
1	3a	2.29	64.85	20	312.82	4	3	0	2	263.22	-0.06
2	3b	2.92	44.62	19	296.82	3	2	0	2	255.18	-0.06
3	3c	1.77	64.85	20	312.82	4	3	0	2	263.22	-0.10
4	3d	1.57	110.67	22	323.37	7	3	0	3	273.02	-0.77
5	3e	1.46	156.50	25	368.37	10	3	0	4	296.36	-0.83
6	3f	0.87	202.32	28	413.37	13	3	1	5	319.69	-1.05
7	3g	1.77	64.85	20	296.37	4	3	0	2	254.62	-0.27
8	3h	1.67	74.08	21	308.40	5	3	0	3	275.23	-0.42
9	3i	1.26	83.31	23	338.43	6	3	0	4	300.78	0.12
10	3j	0.96	95.55	25	368.45	7	3	0	5	326.32	0.15

 

Table 3: Docking score predicted from Mcule the following are the properties of Michael Adducts thiazolidinedione derivatives.

 

RESULT:

Out of 10 proposed chemical structures only best three structures were selected and their energy values are tabulated below. Which were docked with the mentioned targets.

 

 

Table 4:

 

Table 5: Docking score predicted from Mcule the following are the properties of Michael Adducts thiazolidinedione derivatives.

S. No	Code	Substitu-tions	Drug like-liness	Docking score
				Peroxisomal (S)-2-hydroxy acid oxidase(1a17)	UDP-glucose-4-epimerase (1a9y)
1	3a	4-Cl	-0.06	-7.9	-7.8
2	3b	3-Cl	-0.06	-8.8	-7.5
3	3c	2-Cl	-0.10	-7.9	-8.0
4	3d	4-NO2	-0.77	-8.2	-8.1
5	3e	4,3-NO2	-0.83	-8.2	-8.7
6	3f	4,3,2-NO2	-1.05	-7.9	-8.8
7	3g	4-F	-0.27	-8.1	-7.8
8	3h	4-OCH3	-0.42	-7.9	-7.8
9	3i	3,4-OCH3	0.12	-7.9	-7.9
10	3j	4,3,2-OCH3	0.15	-7.2	-8.2

 

Table 6:

 

Docking pose of proposed chemical structures:

 

Figure 3: Docking pose of 3b with the target 1A17

 

Figure 4: Docking pose of 3e with the target 1A9Y

 

 

Figure 5: Docking pose of 3f with the target 1A9Y

 

 

Table 7: Docking score predicted from Mcule the following are the properties of Michael Adducts thiazolidinedione derivatives.

S. No	Code	Substitu-tions	Drug Like-liness	Docking score
				Peroxisomal (S)-2-hydroxy acid oxidase(1a17)	UDP-glucose-4-epimerase (1a9y)
1	3a	4-Cl	-0.06	-7.9	-7.8
2	3b	3-Cl	-0.06	-8.8	-7.5
3	3c	2-Cl	-0.10	-7.9	-8.0
4	3d	4-NO2	-0.77	-8.2	-8.1
5	3e	4,3-NO2	-0.83	-8.2	-8.7
6	3f	4,3,2-NO2	-1.05	-7.9	-8.8
7	3g	4-F	-0.27	-8.1	-7.8
8	3h	4-OCH3	-0.42	-7.9	-7.8
9	3i	3,4-OCH3	0.12	-7.9	-7.9
10	3j	4,3,2-OCH3	0.15	-7.2	-8.2

 

Table 8:

Sr.No.	Code	Substitutions	Ligand: 3f
1	3a	4-Cl
2	3b	3-Cl
3	3c	2-Cl
4	3d	4-NO2
5	3e	4,3-NO2
6	3f	4,3,2-NO2
7	3g	4-F
8	3h	4-OCH3
9	3i	3,4-OCH3
10	3j	4,3,2-OCH3

 

Table 9: Docking score predicted from Mcule the following are the properties of Michael Adducts thiazolidinedione derivatives.

S. No	Code	Substitu-tions	Drug-like-liness	Docking score
				Peroxisomal (S)-2-hydroxy acid oxidase(1a17)	UDP-glucose-4-epimerase (1a9y)
1	3a	4-Cl	-0.06	-7.9	-7.8
2	3b	3-Cl	-0.06	-8.8	-7.5
3	3c	2-Cl	-0.10	-7.9	-8.0
4	3d	4-NO2	-0.77	-8.2	-8.1
5	3e	4,3-NO2	-0.83	-8.2	-8.7
6	3f	4,3,2-NO2	-1.05	-7.9	-8.8
7	3g	4-F	-0.27	-8.1	-7.8
8	3h	4-OCH3	-0.42	-7.9	-7.8
9	3i	3,4-OCH3	0.12	-7.9	-7.9
10	3j	4,3,2-OCH3	0.15	-7.2	-8.2

 

CONCLUSION:

 Based on the literature it has been shown clearly that the compounds 3b,3e,3f have been used to target (a) & (b) receptors where the compound 3b,3e and 3f on docking with the target (a) & (b) produced an energy value of [-8.8],[-8.7] and [-8.8] respectively. Drug likeliness performed in the software of molsoft. Where the drug analog using the “SMILES” notation which are generated by the chem.-sketch. By using the molinspiration online software, the drug analogs are undergone for their molecular properties like milogp, natoms, nON, nOHNH, nViolations, nrotb, Volume, molecular weight, TPSA and Drug likeliness where some of the drug analogs have been shown the good druglikeliness.

 

 

 

ACKNOWLEDGEMENT:

It gives me immense pleasure to express my gratitude to all who helped me directly or indirectly in writing this research work. At the outset, I bow my head in front of the almighty God who bestowed his blessings and enlightened me through all the up’s and down’s which have helped me extend many originally hopeless paths of this project. I am grateful to my supervisor and co-supervisor who have imparted their knowledge about the subject to me to complete this project work. This would not have been a successful effort without their blissful insight and guidance. I acknowledge from the bottom core of my heart, a great debt of gratitude to my beloved parents and colleagues inspiration without which it would not have been possible to accomplish this task.

 

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http://www.acdlabs.com/resources/freeware/chemsketch/

http://molsoft.com/mprop/

http://www.molinspiration.com/cgi-bin/properties

http://www.mcule.in.

 

 

 

 

 

 

 

 

 

 

 

Received on 06.12.2017          Accepted on 18.02.2018        

© Asian Pharma Press All Right Reserved

Asian J. Pharm. Ana. 2018; 8(1):39-44. 

DOI: 10.5958/2231-5675.2018.00007.8