Identification of RdRp inhibitors against SARS-CoV-2 through E-pharmacophore-based virtual screening, molecular docking and MD simulations approaches
Электронный научный архив УРФУ
Информация об архиве | Просмотр оригинала| Поле | Значение | |
| Заглавие |
Identification of RdRp inhibitors against SARS-CoV-2 through E-pharmacophore-based virtual screening, molecular docking and MD simulations approaches
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| Автор |
Rehman, H. M.
Sajjad, M. Ali, M. A. Gul, R. Naveed, M. Aslam, M. S. Shinwari, K. Bhinder, M. A. Ghani, M. U. Saleem, M. Rather, M. A. Ahmad, I. Amin, A. |
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| Тематика |
ADME/T
COVID-19 REAL DATABASE – ENAMINE RNA-DEPENDENT RNA POLYMERASE MM-GBSA 2 CHLORO 3 ISOPROPOXY N [(1 OXO 1,2,3,4 TETRAHYDRO 4 ISOQUINOLINYL)METHYL] BENZAMIDE 4 [[[[ 1 METHYL 2 (1 METHYL 1H IMIDAZOL 2 YL) 6 OXO 3 PIPERIDINYL]METHYL]AMINO] METHYL]BENZAMIDE 5 (3,4,5 TRIMETHOXYPHENYL) 1H PYRAZOLE 3 CARBOHYDRAZIDE N [(2,1,3 BENZOTHIADIAZOL 4 YL) METHYL] 5 [(MORPHOLIN 4 YL) METHYL]PYRIDIN 2 AMINE N [(5 FLUORO 1H BENZIMIDAZOL 4 YL)METHYL] 2 (METHOXYMETHYL) 6 METHYL 4 PYRIMIDINAMINE N2 [2 [1 [[1 METHYL 4 PIPERIDINYL]ACETYL] 3 PIPERIDINYL]ETHYL]GLYCINAMIDE REMDESIVIR RNA DIRECTED RNA POLYMERASE RNA DIRECTED RNA POLYMERASE INHIBITOR UNCLASSIFIED DRUG RNA DIRECTED RNA POLYMERASE ARTICLE COMPLEX FORMATION CONTROLLED STUDY DRUG DETERMINATION DRUG EFFECT DRUG POTENCY DRUG SCREENING DRUG STRUCTURE HIGH THROUGHPUT SCREENING HYDROGEN BOND HYDROPHOBICITY LIGAND BINDING MOLECULAR DOCKING MOLECULAR DYNAMICS NONHUMAN PHARMACOPHORE PROTEIN INTERACTION PROTEIN STABILITY SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2 CORONAVIRUS DISEASE 2019 HUMAN MOLECULAR DOCKING MOLECULAR DYNAMICS PHARMACOPHORE COVID-19 HUMANS MOLECULAR DOCKING SIMULATION MOLECULAR DYNAMICS SIMULATION PHARMACOPHORE RNA-DEPENDENT RNA POLYMERASE SARS-COV-2 |
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| Описание |
The outbreak of novel Coronavirus, an enduring pandemic declared by WHO, has consequences to an alarming ongoing public health menace which has already claimed several million human lives. In addition to numerous vaccinations and medications for mild to moderate COVID-19 infection, lack of promising medication or therapeutic pharmaceuticals remains a serious concern to counter the ongoing coronavirus infections and to hinder its dreadful spread. Global health emergencies have called for urgency for potential drug discovery and time is the biggest constraint apart from the financial and human resources required for the high throughput drug screening. However, computational screening or in-silico approaches appeared to be an effective and faster approach to discover potential molecules without sacrificing the model animals. Accumulated shreds of evidence on computational studies against viral diseases have revealed significance of in-silico drug discovery approaches especially in the time of urgency. The central role of RdRp in SARS-CoV-2 replication makes it promising drug target to curtain on going infection and its spread. The present study aimed to employ E-pharmacophore-based virtual screening to reveal potent inhibitors of RdRp as potential leads to block the viral replication. An energy-optimised pharmacophore model was generated to screen the Enamine REAL DataBase (RDB). Then, ADME/T profiles were determined to validate the pharmacokinetics and pharmacodynamics properties of the hit compounds. Moreover, High Throughput Virtual Screening (HTVS) and molecular docking (SP & XP) were employed to screen the top hits from pharmacophore-based virtual screening and ADME/T screen. The binding free energies of the top hits were calculated by conducting MM-GBSA analysis followed by MD simulations to determine the stability of molecular interactions between top hits and RdRp protein. These virtual investigations revealed six compounds having binding free energies of −57.498, −45.776, −46.248, −35.67, −25.15 and −24.90 kcal/mol respectively as calculated by the MM-GBSA method. The MD simulation studies confirmed the stability of protein ligand complexes, hence, indicating as potent RdRp inhibitors and are promising candidate drugs to be further validated and translated into clinics in future. © 2023
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| Дата |
2024-04-05T16:18:32Z
2024-04-05T16:18:32Z 2023 |
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| Тип |
Article
Journal article (info:eu-repo/semantics/article) |info:eu-repo/semantics/publishedVersion |
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| Идентификатор |
Rehman, HM, Sajjad, MA, Ali, MA, Gul, R, Naveed, M, Aslam, MS, Shinwari, K, Bhinder, MA, Ghani, MU, Saleem, MH, Rather, MA, Ahmad, I & Amin, A 2023, 'Identification of RdRp inhibitors against SARS-CoV-2 through E-pharmacophore-based virtual screening, molecular docking and MD simulations approaches', International Journal of Biological Macromolecules, № 237, 124169. https://doi.org/10.1016/j.ijbiomac.2023.124169
Rehman, H. M., Sajjad, M. A., Ali, M. A., Gul, R., Naveed, M., Aslam, M. S., Shinwari, K., Bhinder, M. A., Ghani, M. U., Saleem, M. H., Rather, M. A., Ahmad, I., & Amin, A. (2023). Identification of RdRp inhibitors against SARS-CoV-2 through E-pharmacophore-based virtual screening, molecular docking and MD simulations approaches. International Journal of Biological Macromolecules, (237), [124169]. https://doi.org/10.1016/j.ijbiomac.2023.124169 0141-8130 Final All Open Access, Bronze, Green https://www.scopus.com/inward/record.uri?eid=2-s2.0-85151298435&doi=10.1016%2fj.ijbiomac.2023.124169&partnerID=40&md5=37789cb6a4ea0a317d404b8a4a4d3c38 https://doi.org/10.1016/j.ijbiomac.2023.124169 http://elar.urfu.ru/handle/10995/130322 10.1016/j.ijbiomac.2023.124169 85151298435 001024410100001 |
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| Язык |
en
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| Права |
Open access (info:eu-repo/semantics/openAccess)
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| Формат |
application/pdf
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| Издатель |
Elsevier B.V.
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| Источник |
International Journal of Biological Macromolecules
International Journal of Biological Macromolecules |
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