2.3.2 Docking evaluation against topoisomerase IV from Klebsiella pneumoniae

Docking studies have been carried out in order to obtain optimized docking conformations of the investigated quinolone derivatives on the crystal structure of topoisomerase IV (PDB ID: 5EIX) from Klebsiella pneumoniae [24]. The binding site and docking pose of the co-crystallized levofloxacin (LFX) ligand, interacting with amino acid residues of the ligand binding site of topoisomerase IV from Klebsiella pneumoniae, are shown in Figure 12a. The levofloxacin was taken as reference ligand to compare the docking results of quinolone derivatives. The docking score, the interacting group, and hydrogen bonds formed with the group interaction atoms of the corresponding amino acids are shown in Table 4. Interactions of quinolone derivatives PQ4 (score: 43.98 and RMSD: 0.05), 6ClPQ4 (score: 41.12 and RMSD: 0.25), PQ11 (score: 48.32 and RMSD: 0.10), HPQ11 (score: 49.57 and RMSD: 0.11), PQ12 (score: 42.76 and RMSD: 0.18), and APQ13 (score: 42.96 and RMSD: 0.32) showed better docking score than that of co-crystalized LFX (score: 37.26 and RMSD: 0.02) as shown in Figures 12b–15a. The most active compound,

#### Figure 8.

(a) Binding site and docking pose of the co-crystallized TTC ligand interacting with the amino acid residues of the ligand binding site of human DNA topoisomerase I. (b) Docking pose of the PQ11 ligand interacting with the amino acid residues of the ligand binding site of human DNA topoisomerase I.

Compounds

26

Dipole moment (Debye)

> PQ4

6ClPQ4

HPQ4 6MePQ4

PQ11 6ClPQ11

HPQ11 6MePQ11

PQ12 6ClPQ12

HPQ12 6MePQ12

PQ13 6ClPQ13

HPQ13 6MePQ13

APQ13 6ClAPQ13

HAPQ13

Table 2. Molecular

 properties for CPK model

computations

 for quinolone compounds.

9.78

13.57

12.11

13.91

5.76

1.32

4.44

6.11

1.74

4.37

5.81

1.49

4.32

5.98

3.01

2.97

11.78

11.19

9.55

11.68

11.16

9.37

6.99

10.10

6.06

3.01

3.05

6.37

3.13

3.24

6.03

3.08

2.95

5.78

1.38

4.40

5.88

1.44

4.44

6.18

1.86

4.32

5.94

1.62

4.32

5.74

1.40

4.34

11.42

9.50

11.77

11.65

11.37

9.67

11.82

5.82

1.46

4.36

6.18

1.89

4.29

5.88

1.62

4.26

5.77

1.43

4.34

5.85

1.47

4.38

5.88

6.24

1.91

4.33

1.62

4.28

 E HOMO (eV) E LUMO (eV)

Molecular properties

HOMO-LUMO

 GAP

Polarizability

 (1030

68.31 69.10 67.89 69.36 72.46 73.27 72.05 73.50 68.57 69.36 68.15 69.64 73.03 73.76 72.60 74.07 71.82 72.62 71.41

69.419

 1.55

 2.59

 2

5

69.491

 1.58

 3.15

 2

5

61.120

 1.56

 2.75

 2

5

83.336

 1.57

 0.43

 1

7

83.520

 1.56

0.06

 1

7

83.732

 1.58

 0.50

 1

7

82.971

 1.57

 0.10

 1

7

44.246

 1.50

 3.70

 1

4

44.658

 1.50

 3.21

 1

4

44.844

 1.52

 3.77

 1

4

44.362

 1.51

 3.37

 1

4

44.271

 1.55

 3.38

 1

4

44.426

 1.54

 4.29

 1

4

44.610

 1.57

 4.84

 1

4

44.195

 1.55

 4.44

 1

4

44.396

 1.51

 3.35

 1

4

Molecular Docking and Molecular Dynamics

44.618

 1.50

 2.76

 1

4

44.864

 1.52

 3.32

 1

4

44.205

 1.51

 2.92

 1

4

m3) PSA (Å2) Ovality

 Log P HBA count HBD count


Ligand Score/

PQ12 52.44/

6ClPQ12 50.48/

HPQ12 51.36/

6MePQ12 52.57/

PQ13 57.18/

6ClPQ13 58.51/

HPQ13 58.40/

6MePQ13 61.22/

APQ13 60.00/

6ClAPQ13 57.07/

HAPQ13 58.14/

29

RMSD (Å)

DOI: http://dx.doi.org/10.5772/intechopen.85970

0.06

0.29

0.37

0.03

0.06

0.09

0.05

0.04

0.06

0.64

0.07

Group interaction/hydrogen bond Bond

O sp<sup>3</sup> from CO2H(OH)-N sp<sup>3</sup> from LYS 374 3.155

O sp<sup>3</sup> from CO2H(OH)-N sp<sup>3</sup> from LYS 374 3.059 O sp<sup>3</sup> from CO2H(CO)-N sp<sup>3</sup> from LYS 374 3.068

O sp<sup>3</sup> from CO2H(OH)-N sp<sup>3</sup> from LYS 374 3.112

O sp<sup>3</sup> from CO2H(OH)-N sp<sup>3</sup> from LYS 374 3.046

O sp<sup>3</sup> from CO2H(OH)-N sp<sup>3</sup> from LYS 374 3.032

O sp<sup>3</sup> from CO2H(OH)-N sp<sup>3</sup> from LYS 374 3.099

O sp3 from CO2H (CO-O sp3 from SER 423 3.059 O sp2 from NO2-N sp2 from ASN 419 2.969

O sp3 from CO2H(OH)-O sp2 from GLU 418 2.978

O sp<sup>3</sup> from CO2H(OH)-N sp<sup>3</sup> from LYS 374 3.008

O sp<sup>3</sup> from CO2H(OH)-N sp<sup>3</sup> from LYS 374 2.934

O sp2 from CO2H(CO)-O sp3 from LYS 425 2.874

GLU 418, GLN 421, LYS 374, THR 498, PHE 361, GLY 363, HIS 367, ARG 364, ARG 362, LYS 493, GLY 365, SER 534, ASP 533, ALA 499, GLY 531, THR 501, and LYS 532

In Silico Drug Design and Molecular Docking Studies of Some Quinolone Compound

GLU 418, GLN 421, GLU 356, LYS 374, THR 498, PHE 361, GLY 363, HIS 367, ARG 364, ARG 362, LYS 493, GLY 365, SER 534, ASP 533, ALA 499, GLY 531, THR 501, and LYS 532

GLU 418, GLN 421, LYS 425, SER 423, LYS 374, THR 498, PHE 361, GLY 363, HIS 367, ARG 364, LYS 493, GLY 365, ILE 420, SER 534, ASP 533, ALA 499, GLY 531, THR 501, and LYS 532

GLU 418, GLN 421, LYS 374, THR 498, PHE 361, ARG 362, GLY 363, HIS 367, ARG 364, LYS 493, GLY 365, SER 534, ASP 533, ALA 499, GLY 531, THR 501, and LYS 532

LYS 425, GLU 418, GLN 421, LYS 374, THR 498, PHE 361, ARG 362, GLY 363, HIS 367, ARG 364, LYS 493, LEU 360, GLY 365, SER 534, ASP 533, ALA 499, GLY 531, THR 501, and LYS 532

GLU 418, GLN 421, LYS 374, THR 498, PHE 361, ARG 362, GLY 363, HIS 367, ARG 364, LYS 493, GLY 365, SER 534, ASP 533, ALA 499, GLY 531, THR 501, and LYS 532

ARG 364, LYS 425, GLY 363, ARG 362, TYR 268, GLN 421, GLU 418, PHE 361, ILE 420, ASN 419, LYS 374, ARG 375, ILE 377, LEU 360, MET 263, SER 423, and TRP 416

O sp<sup>2</sup> from CO2H(CO)-N sp<sup>3</sup> from LYS 425

LYS 425, ARG 364, GLY 365, ASP 533, SER 531, THR 501, ARG 362, PHE 361, LYS 374, LYS 532, GLY 531, ALA 499, HIS 367, THR 498, LYS 493, SER 423, GLN 421, and GLU 418

GLU 418, LYS 425, GLN 421, LYS 374, THR 498, PHE 361, ARG 362, GLY 363, HIS 367, ARG 364, GLY 365, SER 534, ASP 533, ALA 499, GLY 531, THR 501, and LYS 532

LYS 425, ARG 364, GLU 356, GLY 365, ASP 533, GLY 531, THR 501, ARG 362, GLY 363, PHE 361, LYS 374, LYS 532, ALA 499, HIS 367, LYS 493, SER 534, GLN 421, and GLU 41

SER 423, LYS 425, GLN 421, GLU 418, ILE 420, ASN 419, LYS 374, ARG 364, GLY 363, ARG 362, PHE 361, ILE 377, ARG 375, LEU 360, and MET 263

length (Å)

2.989


In Silico Drug Design and Molecular Docking Studies of Some Quinolone Compound DOI: http://dx.doi.org/10.5772/intechopen.85970

Ligand Score/

PQ4 55.35/

6ClPQ4 55.81/

HPQ4 56.08/

6MePQ4 55.52/

PQ11 62.95/

6ClPQ11 63.31/

HPQ11 62.77/

6MePQ11 62.48/

28

TTC D-990

RMSD (Å)

Molecular Docking and Molecular Dynamics

59.15/ 0.14

0.07

0.12

0.10

0.10

0.08

0.12

0.06

0.01

Group interaction/hydrogen bond Bond

O sp<sup>3</sup> from TTC– N sp<sup>2</sup> from ASP 533 3.065 O sp3 from TTC– O sp3 from THR 501 3.166 N sp2 from TTC– N sp<sup>2</sup> from ARG 364 3.353 O sp3 from TTC– O sp2 from GLY 363 3.112 O sp<sup>3</sup> from TTC– N sp2 from GLY 363 3.038

O sp<sup>3</sup> from CO2H(OH)-N sp<sup>3</sup> from LYS 374 3.124

O sp<sup>3</sup> from CO2H(CO)-N sp2 from ARG 364 3.056 O sp3 from CO2H (OH)-O sp2 from GLY 363 2.808 O sp2 from CO-N sp<sup>2</sup> from ARG 364 3.009

O sp<sup>3</sup> from CO2H(CO)-N sp2 from ARG 364 2.782 O sp2 from CO-N sp<sup>2</sup> from ARG 364 2.887

O sp3 from CO2H (OH)-N sp3 from LYS 374 3.040

O sp3 from CO2H (OH)-N sp3 from LYS 374 3.214

O sp3 from CO2H(OH)-O sp2 from GLU 418 2.961

O sp2 from CO2H(OH)-O sp2 from ASP 533 3.144 O sp<sup>3</sup> from CO2H(CO)-N sp2 from ARG 364 3.111 O sp<sup>3</sup> from CO2H(CO)-N sp2 from ARG 364 2.748

O sp3 from CO2H (OH)-N sp3 from LYS 374 3.042

LYS 493, THR 501, LYS 532, GLY 531, ALA 499, THR 498, SER 534, ASP 533, GLY 365, ARG 364, HIS 367, GLY 363, ARG 362, PHE 361, LYS 374, and LEU 360

GLU 418, GLN 421, LYS 374, THR 498, PHE 361, GLY 363, HIS 367, ARG 364, ARG 362, GLY 365, SER 534, ASP 533, ALA 499, GLY 531, THR 501, ASP 500, and LYS 532

LYS 425, TRP 416, ARG 364, GLY 363, ILE 377, ARG 362, PHE 361, LYS 374, ARG 375, LEU 360, MET 263, ILE 420, ASN 419, GLN 421, and GLU 418

ARG 364, LYS 425, GLY 363, ARG 362, GLN 421, GLU 418, PHE 361, ILE 420, ASN 118, LYS 374, ARG 375, ILE 377, LEU 360, and MET 263

GLU 418, GLN 421, LYS 374, THR 498, PHE 361, GLY 363, HIS 367, ARG 364, ARG 362, GLY 365, SER 534, ASP 533, ALA 499, GLY 531, THR 501, and LYS 532

GLU 418, GLN 421, LYS 374, LEU 360, THR 498, PHE 361, GLY 363, HIS 367, ARG 364, ARG 362, LYS 493, GLY 365, SER 534, ASP 533, ALA 499, GLY 531, THR 501, and LYS 532

SER 423, LYS 425, GLN 421, GLU 418, ILE 420, LYS 374, LYS 493, THR 498, LYS 532, GLY 531, THR 501, ASP 533, ALA 499, SER 534, ARG 364, GLY 365, GLY 363, HIS 367, ARG 362, PHE 361, and LEU 360

SER 423, LYS 425, GLN 421, GLU 418, ILE 420, LYS 374, LYS 493, THR 498, LYS 532, GLY 531, THR 501, ASP 533, ALA 499, SER 534, ARG 364, GLY 365, GLY 363, HIS 367, ARG 362, PHE 361, and LEU 360

GLU 418, GLN 421, LYS 374, THR 498, PHE 361, GLY 363, HIS 367, ARG 364, ARG 362, LYS 493, GLY 365, SER 534, ASP 533, ALA 499, GLY 531, THR 501, and LYS 532

length (Å)


### Table 3.

List of docking interactions between the ligand molecules and human DNA topoisomerase I using CLC Drug Discovery Workbench Software.

#### Figure 9.

(a) Docking pose of 6ClPQ 11 ligand interacting with amino acid residues of the ligand binding site of human DNA topoisomerase I. (b) Docking pose of HPQ11 ligand interacting with amino acid residues of the ligand binding site of human DNA topoisomerase I.

Important molecular properties of the investigated compounds, e.g., molecular

(a) Binding site and docking pose of the co-crystallized LFX ligand interacting with the amino acid residues of ligand binding site of the topoisomerase IV. (b) Docking pose of the PQ4 ligand interacting with the amino acid

(a) Docking pose of APQ13 ligand interacting with amino acid residues of the ligand binding site of human DNA topoisomerase I. (b) Overlay of docking poses of all ligands interacting with amino acid residues of the

In Silico Drug Design and Molecular Docking Studies of Some Quinolone Compound

All of the investigated compounds have been docked on human DNA topoisom-

weight, flexible bonds, the number of hydrogen bond donors, the number of hydrogen bond acceptors, and log P, have been calculated. These parameters can be used to evaluate whether a molecule has properties that would make it a likely orally active drug, according to the Lipinski's rule of five [22]. The number of violations of

the Lipinski rules allows to evaluate drug likeness for a molecule (Table 5).

erase (PDB ID: 1K4T) and topoisomerase IV (PDB ID: 5EIX) from Klebsiella

3. Results and discussions

residues of ligand binding site of the topoisomerase IV.

Figure 11.

Figure 12.

31

ligand binding site of human DNA topoisomerase I.

DOI: http://dx.doi.org/10.5772/intechopen.85970

#### Figure 10.

(a) Docking pose of 6MePQ11 ligand interacting with amino acid residues of the ligand binding site of human DNA topoisomerase I. (b) Docking pose of 6MePQ13 ligand interacting with amino acid residues of the ligand binding site of human DNA topoisomerase I.

HPQ11, was predicted to have a significant docking score (49.57) and forms one hydrogen bond with ASP95 (bond length 3.081 Å) (Figure 14a). Docking poses of all quinolone derivatives in the ligand binding site of topoisomerase IV from Klebsiella pneumoniae are shown in Figure 15b.

In Silico Drug Design and Molecular Docking Studies of Some Quinolone Compound DOI: http://dx.doi.org/10.5772/intechopen.85970

#### Figure 11.

(a) Docking pose of APQ13 ligand interacting with amino acid residues of the ligand binding site of human DNA topoisomerase I. (b) Overlay of docking poses of all ligands interacting with amino acid residues of the ligand binding site of human DNA topoisomerase I.

Figure 12.

(a) Binding site and docking pose of the co-crystallized LFX ligand interacting with the amino acid residues of ligand binding site of the topoisomerase IV. (b) Docking pose of the PQ4 ligand interacting with the amino acid residues of ligand binding site of the topoisomerase IV.

Important molecular properties of the investigated compounds, e.g., molecular weight, flexible bonds, the number of hydrogen bond donors, the number of hydrogen bond acceptors, and log P, have been calculated. These parameters can be used to evaluate whether a molecule has properties that would make it a likely orally active drug, according to the Lipinski's rule of five [22]. The number of violations of the Lipinski rules allows to evaluate drug likeness for a molecule (Table 5).

## 3. Results and discussions

All of the investigated compounds have been docked on human DNA topoisomerase (PDB ID: 1K4T) and topoisomerase IV (PDB ID: 5EIX) from Klebsiella

HPQ11, was predicted to have a significant docking score (49.57) and forms one hydrogen bond with ASP95 (bond length 3.081 Å) (Figure 14a). Docking poses of all quinolone derivatives in the ligand binding site of topoisomerase IV from

(a) Docking pose of 6MePQ11 ligand interacting with amino acid residues of the ligand binding site of human DNA topoisomerase I. (b) Docking pose of 6MePQ13 ligand interacting with amino acid residues of the ligand

Klebsiella pneumoniae are shown in Figure 15b.

binding site of human DNA topoisomerase I.

Ligand Score/

6MeAPQ13 56.87/

Discovery Workbench Software.

Table 3.

Figure 9.

Figure 10.

30

RMSD (Å)

Molecular Docking and Molecular Dynamics

0.13

binding site of human DNA topoisomerase I.

Group interaction/hydrogen bond Bond

O sp<sup>3</sup> from CO2H(CO)-O sp3 from SER 423 2.994

O sp2 from CO2H(CO)-N sp3 from LYS 374 3.097

LYS 425, ARG 364, GLY 365, ASP 533, GLY 531, THR 501, ARG 362, GLY 363, THR 498, PHE 361, LYS 374, LYS 532, ALA 499, HIS 367, LYS 493, SER 534, GLN 421, and GLU 418

List of docking interactions between the ligand molecules and human DNA topoisomerase I using CLC Drug

(a) Docking pose of 6ClPQ 11 ligand interacting with amino acid residues of the ligand binding site of human DNA topoisomerase I. (b) Docking pose of HPQ11 ligand interacting with amino acid residues of the ligand

length (Å)


O sp2 from CO-O sp<sup>3</sup> from SER 422 2.993 O sp<sup>2</sup> from CO-N sp2 from SER 422 3.060 O sp2 from CO-N sp2 from ASP 421 3.159

Ligand Score/

33

RMSD (Å)

DOI: http://dx.doi.org/10.5772/intechopen.85970

6MePQ12 35.39/0.17 SER 422, ALA 423, ASP 421, ASP 491, GLY 420, LYS 442, LEU 441, GLY

In Silico Drug Design and Molecular Docking Studies of Some Quinolone Compound

PQ13 38.74/0.19 SER 422, ASP 421, ASP 4921, GLY 420, LYS 422, LEU 441, GLY 443, GLU

6ClPQ13 37.47/0.32 SER 422, ALA 423, ASP 421, GLY 420, ASP 493, ASP 491, LEU 441, GLY

HPQ13 40.08/0.05 HIS 1075, ASP 1079, CYS 1082, VAL 1041, GLY 1078, HIS 1077, SER 1080,

6MePQ13 37.58/0.45 SER 422, ALA 423, ASP 421, ASP 493, ASP 491, GLY 420, LYS 442, LEU

APQ13 42.96/0.32 SER 422, ASP 421, ASP 493, GLY 420, LYS 442, LEU 441, GLY 443, GLU

6ClAPQ13 39.93/0.40 ASP 421, GLY 420, LYS 442, LEU 441, GLY 443, GLU 419, ILE 499, ILE

HAPQ13 37.50/0.50 HIS 1077, ARG 1029, LYS 444, ILE 445, ILE 499, ASP 495, ASP 421, GLU

443, GLU 419, LYS 444, ILE 499, GLY 496, and ASP 495

419, LYS 444, ILE 499, ASP 495, ARG 1029, HIS 1077, SER 1080, ASP 1079, GLY 1079, and HIS 1075

443, GLU 419, LYS 444, ILE 499, GLY 496, and ASP 495

ALA 1081, ARG 1029, LYS 444, ILE 499, ASP 495, ASP 493, GLU 419, LEU, 441, GLY 496, LYS 442, and GLY 443

441, GLY 443, GLU 419, LYS 444, ILE 499, and ASP 495

419, ILE 499, ASP 495, ILE 445, ARG 1029, and HIS 1077

445, LYS 444, ASP 495, ARG 1029, and HIS 1077

419, LEU, 441, GLY 420, LYS 442, and GLY 443

Group interaction/hydrogen bond Bond length

O sp2 from CO-O sp<sup>3</sup> from SER 422 2.943 O sp<sup>2</sup> from CO-N sp2 from SER 422 3.156

O sp2 from CO-N sp<sup>2</sup> from ARG 1029 2.963 O sp2 from CO2H (OH)-N sp2 from ARG 1029 3.081 O sp2 from NO2-O sp2 from SER 1080 2.489

O sp<sup>3</sup> from CO-O sp3 from SER 422 2.664 O sp<sup>2</sup> from CO-N sp2 from SER 422 2.817 O sp2 from CO-N sp2 from ASP 421 3.253

O sp<sup>2</sup> from CO2H(OH)-N sp<sup>2</sup> from CYS 1082 3.241 O sp2 from CO2H (OH)-O sp2 from GLY 1078 2.876

O sp2 from CO-O sp<sup>3</sup> from SER 422 2.797 O sp<sup>2</sup> from CO-N sp2 from SER 422 2.926 O sp2 from CO-N sp2 from ASP 421 3.247

O sp<sup>2</sup> from CO2H(OH)-N sp2 from ARG 1029 2.820 O sp<sup>2</sup> from CO2H(OH)-O sp<sup>2</sup> from ASP 495 3.113 O sp2 from CO2H (OH)-O sp<sup>2</sup> from ASP 495 3.052 N sp3 from NH2-O sp<sup>2</sup> from GLU 419 2.922 N sp<sup>3</sup> from NH2-N sp2 from GLY 443 3.052

O sp<sup>2</sup> from COOH(CO)-N sp2 from ARG 1029 3.063 O sp<sup>2</sup> from COOH(OH)-O sp2 from ASP 495 3.132 N sp3 from NH2-O sp<sup>2</sup> from GLU 419 2.706 N sp<sup>3</sup> from NH2-N sp2 from GLY 443 3.137

O sp<sup>2</sup> from CO2H(OH)-N sp2 from ARG 1029 2.851 O sp<sup>2</sup> from CO2H(OH)-O sp<sup>2</sup> from ASP 495 3.199 N sp3 from NH2-O sp<sup>2</sup> from GLU 419 2.707 N sp<sup>3</sup> from NH2-N sp2 from GLY 443 3.150

(Å)


In Silico Drug Design and Molecular Docking Studies of Some Quinolone Compound DOI: http://dx.doi.org/10.5772/intechopen.85970

Ligand Score/

32

RMSD (Å)

Molecular Docking and Molecular Dynamics

LFX 37.26/0.02 SER 422, ALA 423, ASP 421, GLY 420, LYS 442, LEU 441, GLY 443, GLU

O sp3

PQ4 43.98/0.05 SER 422, ASP 421, GLY 420, GLY 443, GLU 419, ASP 491, LYS 444, ILE

6ClPQ4 41.12/0.25 SER 422, ALA 423, ASP 421, GLY 420, LYS 499, LEU 441, GLY 443, GLU

HPQ4 40.60/0.20 SER 422, ASP 421, GLY 420, GLY 443, GLU 419, ASP 491, LYS 444, ILE

6MePQ4 35.70/0.36 SER 422, ASP 421, GLY 420, GLY 443, GLU 419, ASP 491, LYS 444, ILE

PQ11 48.32/0.10 LYS 444, ILE 499, ASP 495, ASP 493, GLY 443, LEU 441, GLU 419, ASP

6ClPQ11 41.14/0.28 SER 422, ASP 421, GLY 420, LYS 442, LEU 441, GLY 443, GLU 419, LYS

HPQ11 49.57/0.11 HIS 1077, ASP 421, GLY 420, ASP 493, LYS 442, LEU 441, GLU 419, GLY

6MePQ11 39.64/0.18 SER 422, HIS 1077 ASP 421, GLY 420, ASP 491, ASP 493, LYS 442, LEU

PQ12 42.76/0.18 HIS 1077, GLY 420, ASP 493, LYS 442, LEU 441, GLU 419, GLY 443, LYS

6ClPQ12 35.34/0.07 SER 422, ALA 423, ASP 491, ASP 421, GLY 420, LYS 442, LEU 441, GLY

HPQ12 40.45/0.13 SER 422, ALA 423, ASP 421, GLY 420, LYS 442, LEU 441, GLY 443, GLU

419, LYS 444, ILE 499, GLY 496, and ASP 495

499, GLY 496, and ASP 495

419, ASP 491, ASP 493, LYS 444, ILE 499, GLY 496, and ASP 495

499, GLY 496, and ASP 495

499, GLY 496, and ASP 495

491, GLY 420, LYS 442, ASP 421, LEU 567, ALA, 423, SER 422, and GLY 568

444, ILE 499, GLY 496, and ASP 495

443, LYS 444, ILE 499, ILE 445, ASP 495, and ARG 1029

441, GLU 419, GLY 443, LYS 444, ILE 499, ASP 495, ARG 1029, and ILE 445

444, ILE 499, ILE 445, ASP 495, ASP 491, ARG 1029, and GLY 496

443, GLU 419, LYS 444, ILE 499, GLY 496, and ASP 495

419, LYS 444, ILE 499, GLY 496, and ASP 495

Group interaction/hydrogen bond Bond length

O sp2 from CO-O sp<sup>3</sup> from SER 422 2.590 O sp<sup>2</sup> from CO-N sp2 from SER 422 2.856 O sp2 from CO-N sp2 from ASP 421 3.098

from LVF-N sp<sup>2</sup> from GLY 443 3.344

O sp<sup>2</sup> from CO2H(OH)-O sp<sup>3</sup> from GLU 419 2.702

O sp2 from CO-O sp<sup>3</sup> from SER 422 2.870 O sp<sup>2</sup> from CO-N sp2 from SER 422 3.162

O sp<sup>2</sup> from CO2H(OH)-O sp<sup>3</sup> from GLU 419 2.880

O sp2 from CO2 H(OH)-O sp<sup>3</sup> from GLU 419 2.911

O sp<sup>2</sup> from CO2H(OH)-O sp<sup>2</sup> from ASP 491 2.974 O sp<sup>2</sup> from CO2H (OH)-O sp2 from GLU 419 2.606 O sp2 from CO-O sp<sup>3</sup> from SER 422 2.650

O sp2 from CO2H(CO)-N sp2 from ASP 421 3.062

O sp<sup>2</sup> from CO2H(OH)-N sp2 from ASP 495 3.081

O sp<sup>2</sup> from CO2H (OH)-N sp<sup>2</sup> from ASP 495 3.088

O sp2 from CO2H(OH)-O sp2 from ASP 493 2.571 O sp<sup>2</sup> from CO2H (OH)-O sp2 from GLU 419 3.135

O sp2 from CO-O sp<sup>3</sup> from SER 422 2.942 O sp<sup>2</sup> from CO-N sp2 from SER 422 3.185

O sp2 from CO-O sp<sup>3</sup> from SER 422 2.993 O sp<sup>2</sup> from CO-N sp2 from SER 422 3.060 O sp2 from CO-N sp2 from ASP 421 3.159

(Å)


#### Table 4.

List of docking interactions between the ligand molecules and topoisomerase IV (PDB ID: 5EIX) from Klebsiella pneumoniae using CLC Drug Discovery Workbench Software.

Figure 15.

binding site of the topoisomerase IV.

Ligands Atoms Weight

DOI: http://dx.doi.org/10.5772/intechopen.85970

(a) For protein receptor PDB ID: 1K4T. (b) For protein receptor PDB ID: 5EIX.

Ligands with various properties.

Table 5.

35

(Daltons)

(a) Docking pose of APQ13 ligand interacting with amino acid residues of ligand binding site of the topoisomerase IV. (b) Overlay of docking poses of all ligands interacting with amino acid residues of ligand

In Silico Drug Design and Molecular Docking Studies of Some Quinolone Compound

Lipinski violations

TTC 51 418.42 3 0 — 2 8 3.55 — LFX 45 360.36 2 — 01 7 — 1.26 PQ4 46 344.38 4 1 1 1 5 5.34 5.67 6ClPQ4 46 360.83 4 1 1 1 5 5.87 6.20 HPQ4 46 326.39 4 1 1 1 5 5.24 5.57 6MePQ4 49 340.42 4 1 1 1 5 5.60 5.94 PQ11 52 394.44 4 1 1 1 5 5.99 6.52 6ClPQ11 52 410.89 4 1 1 1 5 6.52 7.05 HPQ11 52 376.45 4 1 1 1 5 5.89 6.42 6MePQ11 55 390.47 4 1 1 1 5 6.25 6.78 PQ12 48 346.40 3 1 1 1 5 5.10 5.63 6ClPQ12 48 362.85 3 1 1 1 5 5.63 6.16 HPQ12 48 328.41 3 0 1 1 5 5.00 5.53 6MePQ12 51 342.43 3 1 1 1 5 5.36 5.89 PQ13 51 425.41 4 1 1 1 8 6.08 6.42 6ClPQ13 51 441.86 4 1 1 1 8 6.61 6.94 HPQ13 51 407.42 4 1 1 1 8 5.98 6.31 6MePQ13 54 421.45 4 1 1 1 8 6.35 6.68 APQ13 51 395.43 3 1 1 3 6 5.37 5.90 6ClAPQ13 51 411.88 3 1 1 3 6 5.90 6.43 HAPQ13 51 377.44 3 1 1 3 6 5.27 5.80 6MeAPQ13 54 391.46 3 1 1 3 6 5.63 6.17

Hydrogen donors

Hydrogen acceptors

(a) (b) (a) (b)

Log P

Flexible bonds

#### Figure 13.

(a) Docking pose of 6ClPQ4 ligand interacting with amino acid residues of ligand binding site of the topoisomerase IV. (b) Docking pose of PQ11 ligand interacting with amino acid residues of ligand binding site of the topoisomerase IV.

#### Figure 14.

(a) Docking pose of HPQ11 ligand interacting with amino acid residues of ligand binding site of the topoisomerase IV. (b) Docking pose of PQ12 ligand interacting with amino acid residues of ligand binding site of the topoisomerase IV.

In Silico Drug Design and Molecular Docking Studies of Some Quinolone Compound DOI: http://dx.doi.org/10.5772/intechopen.85970

#### Figure 15.

Ligand Score/

Table 4.

Figure 13.

Figure 14.

34

of the topoisomerase IV.

of the topoisomerase IV.

RMSD (Å)

Molecular Docking and Molecular Dynamics

6MeAPQ13 39.85/0.20 ASP 421, GLY 420, LYS 442, LEU 441, GLU 419, GLY 443, ILE 499, ILE

List of docking interactions between the ligand molecules and topoisomerase IV (PDB ID: 5EIX) from

(a) Docking pose of 6ClPQ4 ligand interacting with amino acid residues of ligand binding site of the topoisomerase IV. (b) Docking pose of PQ11 ligand interacting with amino acid residues of ligand binding site

(a) Docking pose of HPQ11 ligand interacting with amino acid residues of ligand binding site of the topoisomerase IV. (b) Docking pose of PQ12 ligand interacting with amino acid residues of ligand binding site

Klebsiella pneumoniae using CLC Drug Discovery Workbench Software.

445, LYS 444, ASP 495, ARG 1029, and HIS 1077

Group interaction/hydrogen bond Bond length

O sp2 from CO2H(CO)-N sp<sup>2</sup> from ARG 1029 3.154 O sp<sup>2</sup> from CO2H(OH)-O sp<sup>2</sup> from ASP 495 3.115 O sp<sup>2</sup> from CO2H(OH)-O sp<sup>2</sup> from ASP 495 3.252 N sp3 from NH2-O sp<sup>2</sup> from GLU 419 2.705 N sp<sup>3</sup> from NH2-N sp2 from GLY 443 3.132

(Å)

(a) Docking pose of APQ13 ligand interacting with amino acid residues of ligand binding site of the topoisomerase IV. (b) Overlay of docking poses of all ligands interacting with amino acid residues of ligand binding site of the topoisomerase IV.


(a) For protein receptor PDB ID: 1K4T.

(b) For protein receptor PDB ID: 5EIX.

#### Table 5.

Ligands with various properties.

4. Conclusions

DOI: http://dx.doi.org/10.5772/intechopen.85970

Klebsiella pneumoniae.

Acknowledgements

project no. 19-41 01 02.

Conflict of interest

Author details

Bucharest, Romania

37

Lucia Pintilie\* and Amalia Stefaniu

provided the original work is properly cited.

Klebsiella pneumoniae, respectively.

The authors declare no conflict of interest.

The virtual screening of the investigated compounds using docking has been carried out with CLC Drug Discovery Workbench Software and has led to the identification of quinolone derivatives for inhibiting the activities of topoisomerase I and topoisomerase IV. It was observed that the presence of the benzyl substituent in N1 position of the 7-(4-methyl-piperidinyl)-quinolones core leads to increased docking score against human DNA topoisomerase and topoisomerase IV from

In Silico Drug Design and Molecular Docking Studies of Some Quinolone Compound

The compounds PQ11 (1-benzyl-6-fluoro-7-(4-methyl-piperidin-1-yl)-1,4 dihydro-4-oxo-quinolin-3-carboxylic acid), 6ClPQ11 (1-benzyl-6-chloro-7- (4-methyl-piperidin-1-yl)-1,4-dihydro-4-oxo-quinolin-3-carboxylic acid), HPQ11 (1-benzyl-7-(4-methyl-piperidin-1-yl)-1,4-dihydro-4-oxo-quinolin-3-carboxylic acid), and 6MePQ11 (1-benzyl-6-methyl-7-(4-methyl-piperidin-1-yl)-1,4-dihydro-4-oxo-quinolin-3-carboxylic acid) reveal better docking scores than that of the reference ligands, topotecan (TTC) and levofloxacin (LFX), docked on human DNA topoisomerase (PDB ID: 1K4T) and topoisomerase IV (PDB ID: 5EIX) from

This chapter has been financed through the NUCLEU Program, which is implemented with the support of Ministry of Research and Innovation (MCI),

National Institute of Chemical-Pharmaceutical Research and Development,

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: lucia.pintilie@gmail.com

Figure 16. Docking scores of the investigated quinolone compounds targeting human DNA topoisomerase I (PDB ID: 1K4T).

Figure 17.

Docking scores of the investigated quinolone compounds targeting topoisomerase IV (PDB ID: 5EIX) from Klebsiella pneumoniae.

pneumoniae. In case of the molecular docking studies on the human DNA topoisomerase I, all the quinolone derivatives reveal docking scores greater than 50. Only five compounds, e.g., PQ11 (63.31), 6ClPQ11 (62.95), HPQ11 (62.77), 6MePQ11 (62.48), and 6MePQ13 (61.22), reveal better docking scores than that of co-crystallized TTC (59.15) (Figure 16). In case of the molecular docking studies on topoisomerase IV from Klebsiella pneumoniae, only three quinolone derivatives, e.g., 6MePQ4 (35.7), 6ClPQ12 (35.34), and 6MePQ12 (35.39), reveal docking scores less than that of levofloxacin (37.26). The compounds that show better docking scores than that of levofloxacin are HPQ11 (49.57), PQ11 (48.32), PQ4 (43.98), PQ12 (42.76), APQ13 (42.96), and 6ClPQ4 (41.12) (Figure 17). It was observed that the presence of the benzyl substituent in N-1 position of the 7(4-methyl-piperidinyl)-quinolones core leads to increased docking score against human DNA topoisomerase and topoisomerase IV from Klebsiella pneumoniae. The compounds PQ11, 6ClPQ11, HPQ11, and 6MePQ11 reveal better docking scores than that of the reference ligands, topotecan (TTC) and levofloxacin (LFX), docked on human DNA topoisomerase (PDB ID:1K4T) and topoisomerase IV (PDB ID: 5EIX) from Klebsiella pneumoniae, respectively.

In Silico Drug Design and Molecular Docking Studies of Some Quinolone Compound DOI: http://dx.doi.org/10.5772/intechopen.85970
