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Identification of potential riboflavin synthase inhibitors by virtual screening and molecular dynamics simulation studies

Riboflavin synthase is an important enzyme catalyzing the last step of riboflavin biosynthesis in microorganisms. Due to the absolute dependency of the microbes to this biosynthetic pathway coupled with its nonexistence in humans, riboflavin synthase (RiS) is considered as a prospective drug target....

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Main Authors: Mohamad Aris, Sayangku Nor Ariati, Abdul Rahman, Mohd Zulhilmi, Raja Abd Rahman, Raja Noor Zaliha, Mohamad Ali, Mohd Shukuri, Salleh, Abu Bakar, Teo, Chian Ying, Leow, Adam Thean Chor
Format: Article
Language:English
Published: Elsevier 2021
Online Access:http://psasir.upm.edu.my/id/eprint/97605/1/ABSTRACT.pdf
http://psasir.upm.edu.my/id/eprint/97605/
https://www.sciencedirect.com/science/article/pii/S1018364720303839
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spelling my.upm.eprints.976052022-07-25T03:11:10Z http://psasir.upm.edu.my/id/eprint/97605/ Identification of potential riboflavin synthase inhibitors by virtual screening and molecular dynamics simulation studies Mohamad Aris, Sayangku Nor Ariati Abdul Rahman, Mohd Zulhilmi Raja Abd Rahman, Raja Noor Zaliha Mohamad Ali, Mohd Shukuri Salleh, Abu Bakar Teo, Chian Ying Leow, Adam Thean Chor Riboflavin synthase is an important enzyme catalyzing the last step of riboflavin biosynthesis in microorganisms. Due to the absolute dependency of the microbes to this biosynthetic pathway coupled with its nonexistence in humans, riboflavin synthase (RiS) is considered as a prospective drug target. The riboflavin synthase for this study was derived from Leptospira kmetyi, a pathogenic bacterium locally isolated in Malaysia. Leptospirosis, an infectious disease caused by pathogenic Leptospira, is a serious growing public health issue. Treatment of leptospirosis with antibiotics over time resulted in the evolution of antibiotic resistance strains, thus requiring the development of newer but safe antimicrobial agents. In this study, a computational approach involving virtual screening followed by molecular dynamics (MD) simulation was implemented in order to identify possible inhibitors against riboflavin synthase. The model of Leptospira kmetyi riboflavin synthase predicted from E. coli riboflavin synthase (1I8D) was used as the drug target to screen for potential compounds from the ZINC database through virtual screening. The potential compound with the highest Glide score (−10.987 Kcal/mol) was identified to be ZINC21883831. Chemically it is 2-[(2-chloro-4-fluoro-phenyl)methylsulfanyl]-7-phenyl-3,5-dihydropyrrolo[2,3-e]pyrimidin-4-one. The top three docked complexes from the virtual screening and apo-structures were subjected to molecular dynamics simulation to predict the stabilities of the Leptospira kmetyi riboflavin synthase-ligand complexes. Stability parameters including RMSD, RMSF, SASA and Rg of the complexes were evaluated from 60 ns of the MD simulation trajectories. Insights from this study provide promising starting points for the rational designs of new effective and safe anti-leptospirosis drugs. Elsevier 2021 Article PeerReviewed text en http://psasir.upm.edu.my/id/eprint/97605/1/ABSTRACT.pdf Mohamad Aris, Sayangku Nor Ariati and Abdul Rahman, Mohd Zulhilmi and Raja Abd Rahman, Raja Noor Zaliha and Mohamad Ali, Mohd Shukuri and Salleh, Abu Bakar and Teo, Chian Ying and Leow, Adam Thean Chor (2021) Identification of potential riboflavin synthase inhibitors by virtual screening and molecular dynamics simulation studies. Journal of King Saud University - Science, 33 (2). art. no. 101270. pp. 1-39. ISSN 1018-3647 https://www.sciencedirect.com/science/article/pii/S1018364720303839 10.1016/j.jksus.2020.101270
institution Universiti Putra Malaysia
building UPM Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider Universiti Putra Malaysia
content_source UPM Institutional Repository
url_provider http://psasir.upm.edu.my/
language English
description Riboflavin synthase is an important enzyme catalyzing the last step of riboflavin biosynthesis in microorganisms. Due to the absolute dependency of the microbes to this biosynthetic pathway coupled with its nonexistence in humans, riboflavin synthase (RiS) is considered as a prospective drug target. The riboflavin synthase for this study was derived from Leptospira kmetyi, a pathogenic bacterium locally isolated in Malaysia. Leptospirosis, an infectious disease caused by pathogenic Leptospira, is a serious growing public health issue. Treatment of leptospirosis with antibiotics over time resulted in the evolution of antibiotic resistance strains, thus requiring the development of newer but safe antimicrobial agents. In this study, a computational approach involving virtual screening followed by molecular dynamics (MD) simulation was implemented in order to identify possible inhibitors against riboflavin synthase. The model of Leptospira kmetyi riboflavin synthase predicted from E. coli riboflavin synthase (1I8D) was used as the drug target to screen for potential compounds from the ZINC database through virtual screening. The potential compound with the highest Glide score (−10.987 Kcal/mol) was identified to be ZINC21883831. Chemically it is 2-[(2-chloro-4-fluoro-phenyl)methylsulfanyl]-7-phenyl-3,5-dihydropyrrolo[2,3-e]pyrimidin-4-one. The top three docked complexes from the virtual screening and apo-structures were subjected to molecular dynamics simulation to predict the stabilities of the Leptospira kmetyi riboflavin synthase-ligand complexes. Stability parameters including RMSD, RMSF, SASA and Rg of the complexes were evaluated from 60 ns of the MD simulation trajectories. Insights from this study provide promising starting points for the rational designs of new effective and safe anti-leptospirosis drugs.
format Article
author Mohamad Aris, Sayangku Nor Ariati
Abdul Rahman, Mohd Zulhilmi
Raja Abd Rahman, Raja Noor Zaliha
Mohamad Ali, Mohd Shukuri
Salleh, Abu Bakar
Teo, Chian Ying
Leow, Adam Thean Chor
spellingShingle Mohamad Aris, Sayangku Nor Ariati
Abdul Rahman, Mohd Zulhilmi
Raja Abd Rahman, Raja Noor Zaliha
Mohamad Ali, Mohd Shukuri
Salleh, Abu Bakar
Teo, Chian Ying
Leow, Adam Thean Chor
Identification of potential riboflavin synthase inhibitors by virtual screening and molecular dynamics simulation studies
author_facet Mohamad Aris, Sayangku Nor Ariati
Abdul Rahman, Mohd Zulhilmi
Raja Abd Rahman, Raja Noor Zaliha
Mohamad Ali, Mohd Shukuri
Salleh, Abu Bakar
Teo, Chian Ying
Leow, Adam Thean Chor
author_sort Mohamad Aris, Sayangku Nor Ariati
title Identification of potential riboflavin synthase inhibitors by virtual screening and molecular dynamics simulation studies
title_short Identification of potential riboflavin synthase inhibitors by virtual screening and molecular dynamics simulation studies
title_full Identification of potential riboflavin synthase inhibitors by virtual screening and molecular dynamics simulation studies
title_fullStr Identification of potential riboflavin synthase inhibitors by virtual screening and molecular dynamics simulation studies
title_full_unstemmed Identification of potential riboflavin synthase inhibitors by virtual screening and molecular dynamics simulation studies
title_sort identification of potential riboflavin synthase inhibitors by virtual screening and molecular dynamics simulation studies
publisher Elsevier
publishDate 2021
url http://psasir.upm.edu.my/id/eprint/97605/1/ABSTRACT.pdf
http://psasir.upm.edu.my/id/eprint/97605/
https://www.sciencedirect.com/science/article/pii/S1018364720303839
_version_ 1739829916485025792
score 13.211869

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