Molecular Docking Q-SAR Studies of Benzimidazole as Antifungal Nucleus

 

M. Vijey Aanandhi1*, Anbhule Sachin J2

1Department of Pharmaceutical Chemistry and Analysis, School of Pharmaceutical Sciences,

Vels Institute of Science, Technology and Advanced Studies (VISTAS) Chennai - 600117. Tamil Nadu, India.

2Research Scholar, Department of Pharmaceutical Chemistry and Analysis, School of Pharmaceutical Sciences, Vels Institute of Science, Technology and Advanced Studies (VISTAS) Chennai - 600117. Tamil Nadu, India.

*Corresponding Author E-mail: hodpchemistry@velsuniv.ac.in

 

ABSTRACT:

Benzimidazole and its derivatives are used in organic synthesis and vermicides or fungicides as they inhibit the action of certain microorganisms. The molecules to be analysed were aligned on an appropriate template, which is considered to be common substructure. The protein structure of PDB name along with their inhibitor was retrieved from RCSB Protein Data Bank (PDB entry code: 6T1O). The protein structure were subjected to energy minimization and charge calculation (AMBER7FF99), docking score of compounds on 6T1O PDB describe the ligand interaction. Virtual library of benzimidazoles derivatives to find lead structures to test against C. albicans. Twenty compounds were designed in which heterocyclic ring is substituted at NH group of Substituted ortho-phenylenediamine moiety while some compound also bearing chloro and nitro group on para position of aromatic ring.

 

KEYWORDS: Benzimidazole, PDB 6T1O, fungicides, Q-SAR and Docking.

 

 


 

INTRODUCTION:

A crystalline compound benzimidazole (C7H6N2) is used in organic synthesis and inhibits the growth of certain micro-organism. This compound is bicyclic in nature which consists of the fusion of benzene and imidazole1 Nowadays is a moiety of choice which possesses many pharmacological properties. The most prominent benzimidazole compound in nature is N-ribosyl-dimethylbenzimidazole2 which serves as an axial ligand for cobalt in vitamin B12. Benzimidazole, in an extension of the well-elaborated imidazole system, has been used as carbon skeletons for N-heterocyclic carbenes.3

 

Physical properties of Benzimidazole:

The melting point of benzimidazole is 170ºC. It will be noted that the introduction of a substituent into the 1-position in general lowers the melting point.

 

This appears to be due to the fact that benzimidazoles containing hydrogen in the 1- position are associated.4 Benzimidazoles with the imide nitrogen (i.e., hydrogen in the 1-position) are usually more soluble in polar solvents and less soluble in organic solvents.

 

Conversely, the introduction of polar groupings into the molecule increases solubility in polar solvents; thus, 2-aminobenzimidazole is soluble in water.5

 

QSAR:

Quantitative structure-activity and relationships, often simply known as QSAR, is an analytical application that can be used to interpret the quantitative relationship between the biological activities of a particular molecule and its structure. It is considered a major method of chemical researching all over the world today and is frequently used in agricultural, biological, environmental, medicinal, and physical organic studies.6

 

Main objective of QSAR is to observe the biological responses of a set of molecules, measure it, and statistically relate the measured activity to some molecular structure on their surface. The product of QSAR will then produce useful equations, images or models in either 2D or 3D form that would relate their biological responses or physical properties to their molecular structure.

 

Molecular Docking:

The three-dimensional structures known may be represented to show different views of the structures. With complex molecular mechanics programs it is possible to superimpose one structure on another. The same approach is used to superimpose the three-dimensional structure of a potential drug on its possible target site. This process, which is often automated, is known as docking. Molecular docking is used to predict the structure of the intermolecular complex formed between two molecules. The small molecule called Ligand usually interacts with protein’s binding sites. Binding sites are areas of protein known to be active in forming of compounds. There are several possible mutual conformations in which binding may occur. These are commonly called binding modes.7

 

MATERIAL AND METHODS:

In present studies benzimidazole derivatives and their biological activities were taken from previous literatures [Jorg Bauer et.al (2010)]. In order to examine the predictive power of the QSAR models, the dataset was divided into training set consisting of 32 molecules and test set consisting of 8 compounds in such a way that the utilizing the diversity method in such a way that the structural diversity and a wide range of biological activity in the data set were added. The IC50 values were transformed to pIC50 in order to give numerically larger data values.8

 

i.      Docking Analysis: 

Molecular docking studies was carried out using the Surflex Dock module in SYBYL X2.0 software. The  protein structure of pdb name along with their inhibitor was retrieved from RCSB Protein Data Bank (PDB entry code: 6T1O). The protein structure were subjected to energy minimization and charge calculation (AMBER7FF99). After that the known complex Protein structure was used to investigate and validate the docking protocol. All ligands and water molecules were removed. The bloat values was set as 1 and the threshold values as 0.5 for generation of protomol and position was considered to be the active sites for potential receptor’s binding sites.9


 

Table: 1 Docking results: training set and test set

S. N

Compounds

Total Score

Crash

Polar

D-score

Pmf- Score

G-Score

Chem-Score

C-Score

Global-Csore

1

Comp 2

5.49

-1.38

3.52

-133.3

-58.73

-151.8

-27.23

4

4

2

Comp 3

5.64

-1.50

3.54

-128.5

-59.02

-151.1

-26.83

3

3

3

Comp 4

4.57

-0.40

3.47

-101.2

-54.12

-75.46

-19.66

1

1

4

Comp 5

5.73

-1.43

0.92

-146.0

-22.31

-194.0

-21.74

5

5

5

Comp 6

5.05

-1.27

0.37

-109.8

-8.22

-180.0

-19.37

2

2

6

Comp 7

5.09

-1.29

1.39

-128.9

-41.65

-169.3

-24.18

4

4

7

Comp 8

4.78

-0.66

1.43

-120.5

-37.32

-156.5

-18.09

2

2

8

Comp 9

4.60

-1.32

0.93

-131.6

-50.55

-158.1

-24.92

2

2

9

Comp 10*

4.70

-1.30

1.00

-127.9

-51.38

-162.5

-24.40

4

2

10

Comp 11

4.62

-1.57

0.00

-150.0

-27.85

-178.3

-20.19

3

3

11

Comp 12

6.71

-1.81

0.76

-181.5

-18.16

-242.2

-27.79

4

4

12

Comp 13

6.33

-1.06

0.00

-146.7

-44.32

-199.3

-22.60

5

5

13

Comp 14

5.25

-1.37

0.00

-128.5

-27.61

-204.3

-22.24

4

4

14

Comp 15

5.33

-0.81

1.49

-138.3

-46.62

-176.5

-20.15

4

4

15

Comp 16

6.45

-1.71

0.00

-159.8

-36.90

-225.8

-22.65

5

5

16

Comp 17

5.61

-3.20

2.05

-160.2

-17.35

-236.5

-22.05

4

4

17

Comp 18

5.66

-1.65

0.02

-133.1

5.342

-230.1

-21.97

4

4

18

Comp 19

6.16

-1.21

1.61

-141.4

-48.70

-189.5

-24.06

5

5

19

Comp 20

5.79

-1.69

3.68

-133.3

-35.96

-150.3

-21.76

4

4

20

Comp 21*

5.62

-1.08

2.29

-141.8

-40.05

-168.5

-25.95

5

3

21

Comp 22

6.44

-1.50

1.63

-153.0

-46.85

-225.6

-21.39

5

5

22

Comp 23*

5.24

-0.66

2.39

137.4

-26.79

-158.5

-23.71

3

3

23

Comp 24

5.12

-1.11

1.44

-141.0

-27.08

-174.7

-21.90

5

5

24

Comp 25*

5.94

-1.76

1.32

-153.6

-26.74

-224.7

-22.43

4

5

25

Comp 26

5.74

-0.87

1.22

-130.5

-41.83

-181.8

-21.38

4

4

26

Comp 27

5.38

-2.04

1.06

-137.9

-38.80

-164.9

-25.78

5

5

27

Comp 28

4.70

-1.34

0.04

-133.9

-31.41

-165.8

-17.40

4

4

28

Comp 29

6.67

-2.14

1.12

-184.4

-32.20

-249.4

-30.69

5

5

29

Comp 30

5.86

-1.50

1.51

-158.4

-50.42

-238.4

-23.92

5

5

30

Comp 31

5.81

-1.42

0.00

-143.2

1.613

-219.1

-18.44

3

3

31

Comp 32

4.91

-1.04

0.02

-133.1

-15.41

-202.7

-16.52

3

3

32

Comp 33

5.68

-1.73

0.00

-162.0

-46.42

-251.2

-25.91

5

5

33

Comp 34

5.60

-1.81

0.00

-128.9

-33.93

-207.3

-21.47

4

4

34

Comp 35*

6.41

-1.50

1.56

-168.6

-46.59

-230.8

-29.91

4

5

35

Comp 36*

7.32

-2.08

1.70

-171.5

-11.50

-223.9

-29.50

4

4

36

Comp 37

5.40

-0.62

1.51

-141.6

-51.55

-172.8

-20.59

5

5

37

Comp 38*

5.62

-1.50

2.47

-155.9

-51.63

-200.2

-23.43

4

5

38

Comp 39*

5.46

-2.52

0.00

-181.4

-8.280

-247.5

-24.95

3

4

39

Comp 40

5.09

-0.81

0.00

-144.4

-33.29

-197.1

-20.23

4

4

 


 

RESULT AND DISCUSSION:

PDB 6T1O (wild type Candida albican aspartic protease 4 from the fungal parasite bound to an allophenylnorstatine based inhibitor).10

 

Structure of ligand:  Structure of ligand M82 shows Hydrogen bond with two hydrophobic or non polar amino acids i,e Isoleucin (Ile300A) and Phenylalanine (Phe192A)  and with one negatively charged amino acid Aspartate (Asp34A and Asp214A) (two hydrogen bonds) Leucine (Leu 131A) Thyrosine (Thr217A).However the ligand explorer map of ligand M82 shows it has no further hydrophobic interactions.11-14

 

Pose analysis of compound 12 with steric parameter are suggested that phenyl ring and CF3 group attached to it at the 4th position at R1 ,5th position near CN group in phenyl ring and at the 1st position phenyl ring at R2 is not favouring the bulky groups addition, while R3 is supported by addition of bulky groups.

 


 

Fig. 1; CoMSIA contour Maps of compound 12 of Steric(a), Electrostatic(b), Hydrophobic(c), Donor(d), and Acceptor(e).

 

Table: 2 The PLS statistics of CoMFA and CoMSIA models for Anti-fungal activity indicating the best model and field contribution

Statistical parameters

Co MFA

Co MSIA

Field contribution

Co MFA

Co MSIA

q2 (Cross validated)

0.783

0.892

Steric

0.899

0.141

r2

0.834

0.879

Electrostatic

0.401

0.390

F value

51.903

91.279

Donor

-

0.207

SEE

0.021

0.040

Acceptor

-

0.444

Number of component

6

7

Hydrophobic

-

0.119

Pred R2

0.882

0.788

 

 


 

CONCLUSION:

In the present research work docking studies showed that standard drug amphotericin B. Hydrogen bond with two hydrophobic or non polar amino acids i,e Isoleucin (PDB code 6T1O) wild type C. albicnas 4 from the fungal species bound to an allophenylnorstatine based inhibitor, It describes the same approach is used to superimpose the three dimensional structure of a potential drug on its possible target site. In a view of that it was worthwhile to build a virtual library of benzimidazoles derivatives to find lead structures to test against C. albicans. Twenty compounds were designed in which heterocyclic ring is substituted at NH group of Substituted ortho-phenylenediamine moiety while some compound also bearing chloro and nitro group on para position of aromatic ring. Based on this novel designed strategy, the library was docked into C. albicans; fifteen compounds were selected for the synthesis based on their mol dock scores, rerank scores and hydrogen bond interactions.

 

ACKNOWLEDGEMENT:

The authors are grateful to Vels Institute of Science, Technology and Advanced Studies (VISTAS) and its management for providing research facilities and encouragement. I take pleasure to express my sincere thanks to H.S.B.P.V.T’S GOI, College of Pharmacy, Kashti for valuable support.

 

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Received on 05.03.2020            Modified on 22.04.2020

Accepted on 18.05.2020         © RJPT All right reserved

Research J. Pharm. and Tech. 2021; 14(4):2191-2194.

DOI: 10.52711/0974-360X.2021.00388