Shazi Shakil1-3 
,
Adel M Abuzenadah1-3,
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.
This is an Open Access article that uses a funding model which does not charge readers or their institutions for access and distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0) and the Budapest Open Access Initiative (http://www.budapestopenaccessinitiative.org/read), which permit unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited..
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
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