Molecular Docking of

Naphthyl Hydroxamic Acids With DNA

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This chapter deals with the molecular docking of

N-arylhydroxamic acids with DNA. Hex and Argus Lab docking

softwares were used for molecular docking. Both flexible and rigid

docking were performed. Ascore method from Argus Lab and E value

from Hex were employed to obtain binding energies.

MOLECULAR DOCKING OF

NAPHTHYL HYDROXAMIC ACIDS

WITH DNA

CHAPTER V

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Molecular Docking of Naphthyl Hydroxamic Acids with DNA

MOLECULAR DOCKING OF

NAPHTHYL HYDROXAMIC ACIDS WITH DNA

Prediction of the structure and binding free energy of a ligand receptor complex from

structures of the free ligand and receptor only is known as molecular docking.

It is the computational simulation of a candidate ligand binding to a receptor. Receptor is

the large-sized receiving molecule, generally protein, DNA or some other biopolymer.

Ligand is the small-sized molecule binding to the receptor due to structural

complementarity. The three dimensional structure of a potential ligand (drug) is

superimposed on the receptor target site to predict structure of the intermolecular

complexes thus formed. The regions of the receptor involved in complexation are known

as binding sites. Binding may occur in various possible conformations known as binding

modes. It also predicts the strength of the binding and the binding affinity between ligand

and receptor using scoring functions.

TYPES OF DOCKING

(i) Rigid Docking

The internal geometry of the receptor and ligand is kept fixed during docking. It is

also known as Lock and Key type of docking.

(ii) Flexible Docking

An enumeration on the rotations of ligands is performed. The surface cell

occupancy and energy is calculated for every rotation and the optimum pose is

selected. It is also known as induced fit type of docking.

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Molecular Docking of Naphthyl Hydroxamic Acids with DNA

STEPS IN MOLECULAR DOCKING

(i) Building the Receptor

The 3D structure of the receptor can be downloaded from Protein Data Bank

(PDB). The receptor is then processed and water molecules are removed. The

receptor should be biologically stable.

(ii) Identification of the Active Site

The region of the receptor where the ligand has to bind, i.e., the active site should

be identified.

(iii) Ligand Preparation

Ligands can be obtained from the available databases, viz., ZINC, PubChem, etc. It

can be sketched using tools such as Chemsketch or Chemdraw or Marvine

softwares. The ligand should be selected on the basis of the Lipinsky’s rule of 5.

(iv) Docking

The ligand is finally docked with the receptor and the interactions are checked. The

scoring function generates score. The best pose for the ligand with the highest

binding affinity is selected.

DIFFERENT TYPES OF INTERACTIONS

The interactions between ligands and receptors are primarily the consequence of forces

acting between them.

These forces can be of four types:

(i) Electrostatic Forces

These forces originate due to the charges present in the ligand and receptor. They

include charge-charge, charge-dipole and dipole-dipole interactions.

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Molecular Docking of Naphthyl Hydroxamic Acids with DNA

(ii) Electrodynamics Forces

These forces originate due to instantaneous generation of charges, for example, the

Van der Waals interaction.

(iii) Steric Forces

These forces are caused by entropy. For example, in case of low entropy, there may

be forces to minimize the free energy of the system.

(iv) Solvent-Related Forces

These are related to the structural changes of the solvent. They include hydrogen

bond and hydrophobic interactions.

APPLICATIONS

(i) Virtual Screening

Docking combined with a scoring function can be used for quick in silico screening

of large databases of ligands. The ligands that are likely to bind to receptor can be

identified.

(ii) Lead Optimization

Docking predicts the binding mode of a ligand with the receptor. The orientation of

ligand and the groups involved can be known. Thus it can be used to design more

potent and selective analogs.

(iii) Bioremediation

Protein ligand docking can be used to predict pollutants that can be degraded by

enzymes.

In the present investigation, rigid and flexible docking methods were used and carried out

on an Intel core i3 2.4 GHz workstation, 2 GB memory with the Windows operating

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Molecular Docking of Naphthyl Hydroxamic Acids with DNA

system with Argus Lab software. The ligand was drawn in Marvine and converted into

PDB format. The DNA duplex receptor structure was obtained from Protein Data Bank

(PDB No. 1R2L) with 12 base pairs with sequence CCATAATTTACC:

CCTATGAAATCC running in 3′-5′ directions (172). Water molecules were removed

and hydrogen atoms were added to the structure. In docking calculation, Ascore method

from Argus Lab and E value from Hex were employed to obtain binding energies.

Docking based on quantum mechanics was performed on simulation with rigid and

flexible ligand.

(I) DOCKING OF HYDROXAMIC ACIDS WITH DNA BY HEX SOFTWARE

The Hex software is based on Laguiere - Gaussian polynomial order to calculate

translation correlation. Hex 8.0.0 software was used for rigid ligand docking. The ligand

and receptor are superposed through 3D shapes only (173). Docking is performed by

scoring the degree of overlap between pair of grids in 3D. Usually 3D grid based on Fast

Fourier Transform (FFT) correlation algorithm and free grid Spherical Polar Fourier

(SPF) approach, that allow rotational rather than translation correlation are used (174).

The following parameters were used in Hex docking,

Correlation = Shape

FFT = 3D fast filter

Grid = 0.6

Receptor and Ligand range = 180

Distance range = 40

Number of clusters = 200

The result obtained revealed that from Hex docking all hydroxamic acids interact with

DNA through groove binding.

Binding affinities are presented in Table 5.1 as E value.

The best poses obtained by hydroxamic acids upon binding with DNA are shown in

Figures 5.1 to 5.5.

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Molecular Docking of Naphthyl Hydroxamic Acids with DNA

DNA- HYDROXAMIC ACID COMPLEX

ENERGY ( kJ/mol)

N-1-naphthyl-2-methylbenzo- -231.68

N-1-naphthyl-4-methylbenzo- -233.46

N-1-naphthyl-2-ethoxybenzo- -240.38

N-1-naphthyl phenylaceto- -258.40

N-1-naphthyl valero- -214.52

Table 5.1

Binding free energy of DNA-hydroxamic acid complexes obtained through Hex

8.0.0 software.

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Molecular Docking of Naphthyl Hydroxamic Acids with DNA

Figure 5.1: N-1-naphthyl-2-methylbenzohydroxamic acid

Figure 5.2: N-1-naphthyl-4-methylbenzohydroxamic acid

Figure 5.3 : N-1-naphthyl-2-ethoxybenzohydroxamic acid

DOCKING OF HYDROXAMIC ACIDS WITH DNA BY HEX SOFTWARE

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Molecular Docking of Naphthyl Hydroxamic Acids with DNA

Figure 5.4 : N-1-naphthyl phenylacetohydroxamic acid

Figure 5.5 : N-1-naphthyl valerohydroxamic acid

DOCKING OF HYDROXAMIC ACIDS WITH DNA BY HEX SOFTWARE

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Molecular Docking of Naphthyl Hydroxamic Acids with DNA

(II) DOCKING BY ARGUS LAB SOFTWARE

(i) Flexible Docking of Hydroxamic Acids With DNA

Argus Lab docking programe was performed on simultion with flexible ligand docking

and based on quantum mechanics. A spacing of 0.4 Å between the grid point was used,

with docking accuracury ̴ 3Å as root mean of square distance (RMSD).

The binding free energies of the best pose of hydroxamic acids are shown in Table 5.2.

The best poses obtained by hydroxamic acids upon binding with DNA are shown in

Figures 5.6 to 5.10.

Not much difference was found in the binding affinity of the hydroxamic acids with

DNA.

All the compounds show groove binding with DNA.

(ii) Rigid Docking of Hydroxamic Acids With DNA

Rigid ligand docking was performed through Argus Lab software. All the parameters

were kept similar to that of flexible docking.

The binding free energies of the best pose of hydroxamic acids are shown in Table 5.2.

The best poses obtained by hydroxamic acids upon binding with DNA are shown in

Figures 5.11 to 5.15.

Again, not much difference was found in the binding affinity. All the compounds show

groove binding with DNA. The docking results further support the experimental data.

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Molecular Docking of Naphthyl Hydroxamic Acids with DNA

HYDROXAMIC ACID-DNA COMPLEX

ENERGY ( kJ/mol)

FLEXIBLE DOCKING

RIGID DOCKING

N-1-naphthyl-2-methylbenzo- -4.33 -4.02

N-1-naphthyl-4-methylbenzo- -4.28 -1.81

N-1-naphthyl-2-ethoxybenzo- -4.33 -4.24

N-1-naphthyl phenylaceto- -4.18 -3.75

N-1-naphthyl valero- -3.95 -4.63

Table 5.2

Binding free energy of DNA-hydroxamic acid complexes obtained through

ArgusLab.

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Molecular Docking of Naphthyl Hydroxamic Acids with DNA

Figure 5.6 : N-1-naphthyl-2-methylbenzohydroxamic acid

Figure 5.7 : N-1-naphthyl-4-methylbenzohydroxamic acid

Figure 5.8 : N-1-naphthyl-2-ethoxybenzohydroxamic acid

FLEXIBLE DOCKING OF HYDROXAMIC ACIDS WITH DNA BY ARGUS LAB SOFTWARE

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Molecular Docking of Naphthyl Hydroxamic Acids with DNA

Figure 5.9 : N-1-naphthyl phenylacetohydroxamic acid

Figure 5.10 : N-1-naphthyl valerohydroxamic acid

FLEXIBLE DOCKING OF HYDROXAMIC ACIDS WITH DNA BY ARGUS LAB SOFTWARE

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Molecular Docking of Naphthyl Hydroxamic Acids with DNA

Figure 5.6: N-1-naphthyl-2-methylbenzohydroxamic acid

Figure 5.7: N-1-naphthyl-4-methylbenzohydroxamic acid

Figure 5.8: N-1-naphthyl-2-ethoxybenzohydroxamic acid

RIGID DOCKING OF HYDROXAMIC ACIDS WITH DNA BY ARGUS LAB SOFTWARE

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Molecular Docking of Naphthyl Hydroxamic Acids with DNA

Figure 5.9 : N-1-naphthyl phenylacetohydroxamic acid

Figure 5.10 : N-1-naphthyl valerohydroxamic acid

RIGID DOCKING OF HYDROXAMIC ACIDS WITH DNA BY ARGUS LAB SOFTWARE

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Molecular Docking of Naphthyl Hydroxamic Acids with DNA

CONCLUSIONS

All the compounds show DNA binding ability.

The binding affinity for all the compounds calculated through Hex

and Agrus docking softwares is negative showing the spontaneity of

the complexation process.

Both the docking softwares prove that all the compounds under

present study show groove binding mode of DNA interaction.

These results further support the experimental observations.