Computational Screening of Newly Designed Compounds against Coxsackievirus A16 and Enterovirus A71
Outbreaks of hand, foot, and mouth disease (HFMD) that occur worldwide are mainly caused by the Coxsackievirus-A16 (CV-A16) and Enterovirus-A71 (EV-A71). Unfortunately, neither an anti-HFMD drug nor a vaccine is currently available. Rupintrivir in phase II clinical trial candidate for rhinovirus sho...
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| Format: | Article |
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MDPI AG
2022-03-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/6/1908 |
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| author | Amita Sripattaraphan Kamonpan Sanachai Warinthorn Chavasiri Siwaporn Boonyasuppayakorn Phornphimon Maitarad Thanyada Rungrotmongkol |
| author_facet | Amita Sripattaraphan Kamonpan Sanachai Warinthorn Chavasiri Siwaporn Boonyasuppayakorn Phornphimon Maitarad Thanyada Rungrotmongkol |
| author_sort | Amita Sripattaraphan |
| collection | DOAJ |
| description | Outbreaks of hand, foot, and mouth disease (HFMD) that occur worldwide are mainly caused by the Coxsackievirus-A16 (CV-A16) and Enterovirus-A71 (EV-A71). Unfortunately, neither an anti-HFMD drug nor a vaccine is currently available. Rupintrivir in phase II clinical trial candidate for rhinovirus showed highly potent antiviral activities against enteroviruses as an inhibitor for 3C protease (3Cpro). In the present study, we focused on designing 50 novel rupintrivir analogs against CV-A16 and EV-A71 3Cpro using computational tools. From their predicted binding affinities, the five compounds with functional group modifications at P1′, P2, P3, and P4 sites, namely P1′-1, P2-m3, P3-4, P4-5, and P4-19, could bind with both CV-A16 and EV-A71 3Cpro better than rupintrivir. Subsequently, these five analogs were studied by 500 ns molecular dynamics simulations. Among them, P2-m3, the derivative with meta-aminomethyl-benzyl group at the P2 site, showed the greatest potential to interact with the 3Cpro target by delivering the highest number of intermolecular hydrogen bonds and contact atoms. It formed the hydrogen bonds with L127 and K130 residues at the P2 site stronger than rupintrivir, supported by significantly lower MM/PB(GB)SA binding free energies. Elucidation of designed rupintrivir analogs in our study provides the basis for developing compounds that can be candidate compounds for further HFMD treatment. |
| first_indexed | 2024-03-09T13:09:55Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T13:09:55Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-b7c750c30fd74a9aa1d4b8224f66bb662023-11-30T21:43:05ZengMDPI AGMolecules1420-30492022-03-01276190810.3390/molecules27061908Computational Screening of Newly Designed Compounds against Coxsackievirus A16 and Enterovirus A71Amita Sripattaraphan0Kamonpan Sanachai1Warinthorn Chavasiri2Siwaporn Boonyasuppayakorn3Phornphimon Maitarad4Thanyada Rungrotmongkol5Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, ThailandStructural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, ThailandDepartment of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, ThailandApplied Medical Virology Research Unit, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, ThailandResearch Center of Nano Science and Technology, Shanghai University, Shanghai 200444, ChinaStructural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, ThailandOutbreaks of hand, foot, and mouth disease (HFMD) that occur worldwide are mainly caused by the Coxsackievirus-A16 (CV-A16) and Enterovirus-A71 (EV-A71). Unfortunately, neither an anti-HFMD drug nor a vaccine is currently available. Rupintrivir in phase II clinical trial candidate for rhinovirus showed highly potent antiviral activities against enteroviruses as an inhibitor for 3C protease (3Cpro). In the present study, we focused on designing 50 novel rupintrivir analogs against CV-A16 and EV-A71 3Cpro using computational tools. From their predicted binding affinities, the five compounds with functional group modifications at P1′, P2, P3, and P4 sites, namely P1′-1, P2-m3, P3-4, P4-5, and P4-19, could bind with both CV-A16 and EV-A71 3Cpro better than rupintrivir. Subsequently, these five analogs were studied by 500 ns molecular dynamics simulations. Among them, P2-m3, the derivative with meta-aminomethyl-benzyl group at the P2 site, showed the greatest potential to interact with the 3Cpro target by delivering the highest number of intermolecular hydrogen bonds and contact atoms. It formed the hydrogen bonds with L127 and K130 residues at the P2 site stronger than rupintrivir, supported by significantly lower MM/PB(GB)SA binding free energies. Elucidation of designed rupintrivir analogs in our study provides the basis for developing compounds that can be candidate compounds for further HFMD treatment.https://www.mdpi.com/1420-3049/27/6/1908hand foot and mouth diseasecoxsackievirus A16enterovirus A713C proteasein silico drug design |
| spellingShingle | Amita Sripattaraphan Kamonpan Sanachai Warinthorn Chavasiri Siwaporn Boonyasuppayakorn Phornphimon Maitarad Thanyada Rungrotmongkol Computational Screening of Newly Designed Compounds against Coxsackievirus A16 and Enterovirus A71 Molecules hand foot and mouth disease coxsackievirus A16 enterovirus A71 3C protease in silico drug design |
| title | Computational Screening of Newly Designed Compounds against Coxsackievirus A16 and Enterovirus A71 |
| title_full | Computational Screening of Newly Designed Compounds against Coxsackievirus A16 and Enterovirus A71 |
| title_fullStr | Computational Screening of Newly Designed Compounds against Coxsackievirus A16 and Enterovirus A71 |
| title_full_unstemmed | Computational Screening of Newly Designed Compounds against Coxsackievirus A16 and Enterovirus A71 |
| title_short | Computational Screening of Newly Designed Compounds against Coxsackievirus A16 and Enterovirus A71 |
| title_sort | computational screening of newly designed compounds against coxsackievirus a16 and enterovirus a71 |
| topic | hand foot and mouth disease coxsackievirus A16 enterovirus A71 3C protease in silico drug design |
| url | https://www.mdpi.com/1420-3049/27/6/1908 |
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