Electronic Descriptor Based Qsar and Docking Studies of Some 2-[5-(Aryloxymethyl)-1, 3, 4-Oxadiazol-2-Yl- sulfanyl] Acetic Acids as Anti-P.Aeruginosa

Molecular parameters of 2-[5-(aryloxymethyl)-1, 3, 4-oxadiazol-2-ylsulfanyl] acetic acids and it derivatives were calculated using density Functional theory (DFT). Quantitative Structure Activity Relationship (QSAR) was developed for the antimicrobial activity of the compounds while the interaction between the compounds and the receptor (4r0s) was studied using docking method. We report the molecular electronic descriptors for anti-P.aeruginosa activities of the seven compounds. Using the developed QSAR models, the predicted bioactivity (IC50) of the compounds fitted well with the experimentally observed IC50. In addition, ligand-receptor interactions are reported and 2-(5-((4-nitrophenoxy) methyl)-1, 3, 4-oxadiazol-2-ylsulfanyl) acetic acid (A7) showed the greatest affinity to bind on the active site of P. aeruginosa cell line


Introduction
Bacterial resistance to antibiotics remain a great threat to human health globally. Antibiotic resistance has been responsible for increasing bacterial infections among the young and the old [1] . There are still continuous great effort that are devoted to finding new and more efficient antibiotics that can supress the defence system of bacteria [2] . Therefore, it is in the search for new antimicrobial drug that can offer new pathway of action to solve the problem of multi-drug resistance that Neelam and co-workers (2016) [3] synthesized a number of 2-[5-(aryloxymethyl)-1, 3, 4-oxadiazol-2-ylsulfanyl] acetic acids with antibacterial properties against P.aeruginosa.
Pseudomonas aeruginosa is a bacterial pathogen that is metabolically resourceful. It can cause obstinate health issue in patients with blister and forfeited immune system [4] . Pseudomonas aeruginosa also inhabits the surface of living things, such as animals, vegetation and human being [5] . It is a gram-negative bacteria and it is a cause of many infections like nosocomial infection, chronic airway infections etc [6] . It easily adapt to any change in location and only require few nutrients to grow and develop defence against antibiotics [7] .
Furthermore, biological activities of compounds depend on their structure and electronic properties. Computational methods afford the opportunity to obtain information on the most stable conformation and electronic parameters of organic molecules. We therefore undertake in this work, computational investigation of the synthesized substituted acetic acids with a view to developing a quantitative structure activity relationship (QSAR) for these compounds and their antibacterial action on Pseudomonas aeruginosa.

Computational details Electronic descriptors and QSAR studies:
Optimization of seven compounds was performed using 6-31(d,p) basis set so as to obtain molecular descriptors for anti-P.aeruginosa activity of 2-[5-(aryloxymethyl)-1, 3, 4-oxadiazol-2-ylsulfanyl] acetic acids and its analogues. The optimization was achieved using quantum chemical software i.e. Spartan '14 by wave function-Inc (Spartan 14) [16] . Also, QSAR model were developed using selected molecular descriptors in order to probe into biological activities of the studied compounds [17] . The development of the QSAR model was achieved by using multiple linear regression method and this was validated using cross validation (R 2 ) and adjusted R 2 (Equation 1 and 2).
The R2 adjusted could be calculated using equation (2) Furthermore, docking study was performed for observing binding energy and non-bonding interaction between the optimized molecules and the P.aeruginosa cell line, MTCC 2453 receptor, (PDB ID: 4r0s). The software used for docking study were; Discovery Studio, Autodock tool, AutoDockvina and Edupymol version 1.7.4.4.

Result and Discussion
Molecular descriptors and QSAR studies: The optimized structures of the compounds are shown in Figure 1, while the calculated molecular descriptors are given in Table 1. A QSAR investigation was executed to observe the structure activity relationship of seven 2-[5-(aryloxymethyl)-1, 3, 4-oxadiazol-2-ylsulfanyl] acetic acids derivatives with antibacterial properties. In QSAR studies, fitting and predictability are a function of the quality of a developed QSAR model [18] . Also, the development of QSAR model require dependent and independent variables via statistical analysis. In this work, the dependent variable was chosen to be P.aeruginosa cell line and the calculated parameters (Table 1)  The result given in Table 2 and Table 3 show that the model reproduced the observed IC 50 and this demonstrated the quality and the predicting power of the developed QSAR model. However, replicating power of the developed QSAR model, confirmed through their correlating coefficient (R 2 ), is not enough to justify the actual efficacy of any QSAR model, hence, the stability of the model could be confirmed by considering cross-validation method and adjusted R 2 . The obtained CV. R 2 as shown in Table  3 proved that the model is reliable and fitting since it is greater than the standard (0.5) [19,20] . Also, the value obtained for adjusted R 2 was greater than the standard (0.6) which showed the effectiveness of the model. As shown in Table 2    Docking studies: In this work, a modest assessment of the conformation of P.aeruginosa cell line (PDB ID: 4r0s) was observed using Ramachandran plot. As shown in Figure 2, the protein used in this work is stable and is of a good quality. The seven molecular compounds were docked on the active gouge of P.aeruginosa cell line (PDB ID: 4r0s) and the outcome are shown on Table 4. As displayed on Table 4, the binding energy for each complex were ranged from -5.20 to -5.60 kcal/mol and this revealed that A7 had the greatest affinity to bind to the active site of P.aeruginosa cell line with a binding energy of -5.60 kcal/ mol. Nine conformations each were observed for the docking simulation of individual ligand-receptor complex and figure 3 shows the residue involved in the interaction between A 7 and 4r0s. In the complex formed between A 7 and the receptor, TYR-50, PRO-45 and ASN-48 formed coordination and hydrogen bond (with bond distance 2.1Å, 2.9Å and 2.8Å) with O 3 , O 4 and O 4 of carboxylic acid of oxadiazole ring respectively. Also, LEU-61 formed hydrogen bond with O 5 of nitro group of nitrobenzene twice and O 6 of nitro group of nitrobenzene with bond distance 2.6Å, 3.1Å and 3.1Å respectively.