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Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

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Open Access  Full Text Article                                                                                                                                                                                               Research Article

Novel 1, 3, 4-Oxadiazole-pyridine hybrids as potential DNA gyrase B inhibitors (5D7R): ADMET prediction and molecular docking study

Nagaraj N Durgadasheemi*[1], Shivanand N Kolageri*²

¹ Department of Pharmaceutical Chemistry, R R College of Pharmacy, Chikkabanavar, Bengaluru-560090 Karnataka, India

² Department of Pharmaceutical Chemistry, BLDEA’s SSM College of Pharmacy and Research Centre, Vijayapur-586103, Karnataka, India

INTRODUCTION:

Traditional methods for finding innovative therapeutic medicines were very expensive, time-consuming, and possibly less effective. Virtual screening, supported by the presentation of structural information, is a rational and straightforward strategy that is introduced to solve the shortcomings of existing strategies. Virtual screening techniques are frequently categorised as structure- and ligand-based drug design methodologies. While ligand-based tactics address quantitative structure activity relationship (QSAR) and pharmacophore modelling, the structure-based drug approach discusses molecular tying up ¹. The molecular docking method determines how a chemical interacts with a target molecule. By identifying the preferred orientation of the least free energy, it predicts the affinity of molecules for binding to form a stable complex with the supermolecule ². For the most part, Shape Complementarity and Simulation are the two fundamental techniques used in molecular docking.

Figure 1 Computer-aided drug design

1,3,4‐Oxadiazole is a 5‐membered planar aromatic group represents affluent heterocyclic group and its derivatives have played a major role in the pharmaceutical chemistry. 1,3,4-Oxadiazole derivatives are the heterocyclic that have received considerable attention during the last two decades as they possess wide range of biological properties include antibacterial³, antituberculosis⁴, anti‐inflammatory⁵, antifungal⁶, analgesic⁷, anticancer⁸, immunosuppressive⁹, anticonvulsant^10], and tyrosinase inhibitor^.11

MATERIALS AND METHODS:

Software required:

The study of molecular docking was conducted on a computer equipped with the computational tools swiss dock, PyRx, and Biovia discovery studio visualizer tools (HP Pavilion AMD RyzenTM 5 Hexa Core 5500 APU @ 2.1GHz with turbo boost up to 4GHz Processor version 5500U and 16.00 GB RAM with 64-bit Windows-11 operating system).

Ligand and macromolecule preparation:

The chemical structures of the ligands utilised in this work were created and optimised using the free Chemsketch 2021 programme, and they were stored in mol format before being translated to PDB format by Open Bable 2.3.2, which was necessary for PyRx software execution. Before beginning the molecular docking procedure, the target enzyme was prepped by removing the natural ligand and water molecules that were linked to it. After that, the investigation ligand was loaded with hydrogen atoms added, their torsions and rotatable bonds were assigned, and the files were saved as ligand pdbqt.

Figure. No: 2

Ligand Identification:

The ligands were 1,3,4-oxadiazole derivatives (Table-2). Azithromycin, ciprofloxacin, and amoxicillin are some of the contemporary antibacterial medications. They were obtained from the drug bank database and used in comparison and docking investigations (Table-1). The Open Babel application was used to download the known structures in SDF format and convert them to PDB format. The next step was to conduct docking research using PyRx and the Biovia Discovery Studio visualizer tools.

In silico ADME (Absorption, Distribution, Metabolism and Excretion Studies):

ADME describes the pharmacokinetics of substances in an organism's body. It assesses the danger associated with administering a pharmaceutical substance to an individual or another creature. Pre ADMET (https://preadmet.bmdrc.kr/), Swiss ADME (http://www.swissadme.ch/), and other online tools are used to identify these pharmacokinetic features in silico. The molecules become inactive when there are two or more violations of Lipinski's rule of five. To assess whether a molecule is similar to existing drugs on the market, a complex balancing act involving several chemical properties and structural traits must be performed.

In this way, the 16 different conformers were generated (Figure-2) and blind docking was performed to know whether these molecules bind in the active site or anywhere in the target was demonstrated by the biovia discovery studio program.

Table-1 Showing Structure and Standard of known drug.

Table-2 Showing structures of 1,3,4-oxadiazole derivatives used as ligands. (4a-4p)

RESULTS AND DISCUSSION:

Absorption, distribution, metabolism and excretion (ADME results:

We can say that the molecules are orally active because all the created compounds adhere to the same rule. Tables 3 and 4 present the findings of ADME investigations. The octanol water partition coefficient (mol log P) of the proposed compounds must not be larger than 5. The compounds' good oral bioavailability is indicated (Table 3). The logarithm of molar concentration is used to represent the water solubility. The usual range for the skin permeability of designed compounds is between -5.50 to -6.07 cm/s. The suggested compounds are only moderately water-soluble because they have lipophilic functionalities intended to increase cell permeability. Using a volume of distribution, blood-brain barrier permeability, and fraction unbound, the drug's distribution in the body was estimated. A higher value for the volume of distributions denotes a better drug distribution in tissues compared to plasma, and a log volume of distributions value greater than 0.40 denotes a greater tissue distribution.

Table-3: Drug likeness analysis of designed 1,3,4-Oxadiazole derivatives (4a-4p)

^aMW: molecular weight, ^bTPSA: total polar surface area, ^cmiLogP: molinspiration partition coefficient, ^d%Abs: %Abs = 109 − (0.345 × TPSA), ^enviol: number of violations, ^fnrotb: number of rotatable bonds, H_A: number of hydrogen bond acceptors, H_D: number of hydrogen bond donors.

Table-4: In silico ADME properties of 1,3,4-Oxadiazole designed derivatives. (4a-4p)

Molecular docking results:

The target antibacterial drug discovery In-silico docking study of 16 compounds gave us an idea about the derivatives responsible for anti-microbial activity. The obtained results indicated that all studied ligands have similar positions and orientation inside the putative binding site of crystal structure DNA gyrase B receptors or (PDB ID: 5D7R) which reveals a large space bounded by a membrane-binding domain which serves as an entry channel for substrate to the active site. In addition, the affinity of any small molecule can be considered as a unique tool in the field of drug design. There is a relationship between the affinity of organic molecules and the free energy of binding. This relationship can contribute in the prediction and interpretation of the activity of the organic compounds toward the specific target protein and may be the possible mechanism by which derivatives displayed their anti-microbial activity as on this protein constituent are most appropriately docked.

Based on the docking binding score of the 4m and 4n compounds has resulted in a good binding affinity score of -8.1kcal/mol in comparison to the other derivatives and also it exhibited that activity approx. nearly with the standard drug amoxicillin of -7.11kcal/mol. The same 5D7R protein has interacted with the 4m and 4n compounds in comparison with standard amoxicillin drugs having better therapeutic activity. The various residues of amino acids (e.g., ILE175, ILE51, GLU58, ILE86, SER55, ASP51, PRO87, ARG84, ARG144, GLY85, GLU58,) have interacted with the 4m and 4n scaffolds. The standard amoxicillin has interacted similarly with some of the amino acid residues (ARG84, SER55, GLU58, ILE86, ILE179).

Table-5: Docking score of the designed 1,3,4-Oxadiazole derivatives.

Acknowledgement: The authors are thankful to Principal “Department of Pharmaceutical Chemistry” R R College of Pharmacy, Chikkabanavar, Bengaluru-560090 Karnataka and BLDEA’s SSM College of Pharmacy and Research Centre, Vijayapur-586103, Karnataka for encouraging throughout the research work.

Conflict of Interest: The authors declare that no financial or commercial ties that might be viewed as creating a conflict of interest existed throughout the research.

AUTHOR CONTRIBUTION:

Nagaraj N Durgadasheemi and Shivanand N Kolageri both did a proper literature survey, collected data, design the work, and wrote a portion of paper and provided maximum effort in the correction, both did a proper design the manuscript. Shivanand N Kolageri Conceived and design the analysis. The final draft was checked by all the authors. 

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Corresponding Author:

[1]^* Nagaraj N Durgadasheemi, Pharmaceutical Chemistry, R R College of Pharmacy, Chikkabanavar, Bengaluru-560090 Karnataka, India,                                                              E-mail address: nag11.nd@gmail.com Tel: + 91-9916209962

^2*Shivanand Kolageri, Pharmaceutical Chemistry, BLDEA’s SSM College of Pharmacy and Research Centre, Vijayapur-586103, Karnataka, India,                                                                    E-mail address: shivanandkolageri1996@gmail.com  Tel: + 91-8904312073