Tropical Journal of Pharmaceutical Research

Original Research Article | OPEN ACCESS

Identification of a putative anti-rheumatoid arthritis molecule by virtual screening

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

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

For correspondence:- Shazi Shakil Email: sfaruqi@kau.edu.sa

Accepted: 20 May 2020 Published: 30 June 2020

Citation: Shakil S, Attar SM, Abuzenadah AM, Fathaldin O, Al-Raddadi R, Sulaiman MI. Identification of a putative anti-rheumatoid arthritis molecule by virtual screening. Trop J Pharm Res 2020; 19(6):1255-1261 doi: 10.4314/tjpr.v19i6.21

© 2020 The authors.
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Abstract

Purpose: To propose an improved chemical skeleton whose scaffolds could be used for the design of future thymidylate synthase (TS)-inhibitors against rheumatoid arthritis.

Methods: The drug discovery platform, ‘MCULE’, was employed for inhibitor-screening. The ‘methotrexate-interaction site’ in the crystal (PDB ID 5X66) was used as a target. One ‘RO5 violation’ was permitted. A maximum of ‘10 rotatable bonds’ and ‘100 diverse molecules’ were also allowed in the protocol. The ‘threshold similarity cut off’ was 0.7. The input values describing the remaining parameters were kept as ‘default’. The ‘Open Babel Linear Fingerprint’ was used for the analyses of molecular descriptors, followed by ADME-check.

Results: 4-(4-Methyl-1-piperazinyl)-2-phenyl[1]benzofuro[3,2-d]pyrimidine corresponding to the MCULE ID-7590816301-0-93 exhibited the overall best binding with TS. The free energy of binding was -8.6 kcal/mol. A total of 17 amino acid residues were significant for the binding interactions. Importantly, 9 residues were common to methotrexate binding. It satisfied pertinent ADME conditions.

Conclusion: 4-(4-Methyl-1-piperazinyl)-2-phenyl[1]benzofuro[3,2-d]pyrimidinemay emerge as a potent seed molecule for TS-inhibitor design in the context of rheumatoid arthritis. It has satisfied pertinent ADME features. However, there is need for further wet laboratory validation.

Keywords: Anti-rheumatoid arthritis, Inhibitor design, Methotrexate, Seed molecule, Thymidylate synthase, Virtual screening