Tropical Journal of Pharmaceutical Research

Original Research Article | OPEN ACCESS

Molecular interaction of 4-amino-N’-(benzoyloxy)-N-(2,4-dimethylphenyl)-1,2,5-oxadiazole-3-carboximidamide with the methotrexate binding site of human DHFR, and its implication in rheumatoid arthritis

Shazi Shakil^1-3 , Adel M Abuzenadah^1-3, Suzan M Attar⁴, Omar Fathaldin⁴, Rajaa Al-Raddadi⁵, Mansour I Sulaiman⁶

¹King Fahd Medical Research Center, King Abdulaziz University; ²Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University; ³Center of Excellence in Genomic Medicine Research, King Abdulaziz University; ⁴Rheumatology Department, King Abdulaziz University; ⁵Department of Community Medicine, Faculty of Medicine, King Abdulaziz University; ⁶Department of Pharmacology, College of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.

For correspondence:- Shazi Shakil Email: shazibiotech@gmail.com

Accepted: 27 April 2020 Published: 31 May 2020

Citation: Shakil S, Abuzenadah AM, Attar SM, Fathaldin O, Al-Raddadi R, Sulaiman MI. Molecular interaction of 4-amino-N’-(benzoyloxy)-N-(2,4-dimethylphenyl)-1,2,5-oxadiazole-3-carboximidamide with the methotrexate binding site of human DHFR, and its implication in rheumatoid arthritis. Trop J Pharm Res 2020; 19(5):1045-1052 doi: 10.4314/tjpr.v19i5.20

© 2020 The authors.
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Abstract

Purpose: To identify an improved lead molecule for the human dihydrofolate reductase (DHFR) inhibition that ‘sits’ in the same binding cavity as methotrexate by high throughput computational screening.

Methods: The 3-D structure of the DHFR binding site was examined using ‘CASTp3.0’. Structure based in silico screening of about 5 million drug candidates housed in the MCULE database was performed. The obtained molecule-hits were ranked in accordance with their VINA scores, made to pass through drug-likeness filters, ΔG cut-off criterion, toxicity-checker and finally ‘zero RO5 criterion’.

Results: The ‘top molecule’, namely, 4-amino-N'-(benzoyloxy)-N-(2,4-dimethylphenyl)-1,2,5-oxadiazole-3-carboximidamide, displayed robust binding with human DHFR through 21 amino acid residues (ΔG = -9.6 kcal/mol) while 10 of these residues were the same as those displayed by ‘methotrexate binding interactions’. It passed through relevant drug screening filters including the ‘Toxicity Checker’.

Conclusion: This research work describes the molecular interaction of human DHFR with an improved lead molecule named, 4-amino-N’-(benzoyloxy)-N-(2,4-dimethylphenyl)-1,2,5-oxadiazole-3-carboximidamide, with a ΔG of -9.6 kcal/mol, thus satisfying adequate ADME features for further in vitro and in vivo validation in the context of rheumatoid arthritis.

Keywords: Dihydrofolate reductase, In silico screening, Methotrexate, Rheumatoid arthritis, DHFR