Department of Bioinformatics, Shaheed Benazir Bhutto Women University, Peshawar, Pakistan.
Department of Bioinformatics, Shaheed Benazir Bhutto Women University, Peshawar, Pakistan.
Eur J Pharmacol. 2020 Oct 15;885:173496. doi: 10.1016/j.ejphar.2020.173496. Epub 2020 Aug 22.
The rapid breakout of the coronavirus disease of 2019 (COVID-19) has been declared pandemic with serious global concern due to high morbidity and mortality. As we enter the phase beyond limitations there is an urgent need for explicit treatment against COVID-19. To face this immediate global challenge, drug development from scratch is a lengthy process and unrealistic to conquer this battle. Drug repurposing is an emerging and practical approach where existing drugs, safe for humans, are redeployed to fight this harder to treat disease. A number of multi clinical studies have repurposed combined cocktail (remdesivir + chloroquine and favipiravir + chloroquine) to be effective against COVID-19. However, the exact mechanistic aspect has not yet been revealed. In the present study, we have tried to decipher the mechanistic aspects of existing medicines at the viral entry and replication stage via the structural viroinformatics approach. Here we implied the molecular docking and dynamic simulations with emphasis on the unique structural properties of host receptor angiotensin-converting enzyme 2 (ACE2), SARS-CoV2 spike protein and RNA dependent RNA polymerase enzyme (RdRp) of the SARS-CoV2. Deep structural analysis of target molecules exposed key binding residues and structural twists involved in binding with important pharmacophore features of existing drugs [(7-chloro-N-[5-(diethylamino)pentan-2-yl]quinolin-4-amine (chloroquine),N-[[4-(4-methylpiperazin-1-yl)phenyl]methyl]-1,2-oxazole-5-carboxamide N-[[4-(4-methylpiperazin-1-yl)phenyl]methyl]-1,2-oxazole-5-carboxamide) (SSAA09E2), 2-ethylbutyl (2S)-2-{[(S)-{[(2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-5-cyano-3 (remdesivir) and 6-Fluor-3-oxo-3,4-dihydro-2-pyrazincarboxamid (favipiravir)]. It is evident from this structural informatics study that combo of chloroquine + SSAA09E2 with remdesivir or favipiravir could significantly restrain the virus at the entry and replication stage. Thus, drug repurposition is an attractive approach with reduced time and cost to treat COVID-19, we don't have enough time as the whole world is lockdown and we are in urgent need of an obvious therapeutics' measures.
新型冠状病毒病（COVID-19）的迅速爆发引起了全球严重关注，因其发病率和死亡率高而被宣布为大流行。随着我们进入限制之外的阶段，迫切需要针对 COVID-19 的明确治疗方法。为了应对这一直接的全球挑战，从头开始开发药物是一个漫长的过程，而且不切实际，无法征服这场战斗。药物再利用是一种新兴的实用方法，其中现有的、对人类安全的药物被重新用于治疗这种更难治疗的疾病。许多多临床研究已经将联合鸡尾酒（瑞德西韦+氯喹和法匹拉韦+氯喹）重新用于治疗 COVID-19。然而，确切的机制方面尚未揭示。在本研究中，我们试图通过结构病毒信息学方法在病毒进入和复制阶段破译现有药物的机制方面。在这里，我们通过分子对接和动态模拟强调了宿主受体血管紧张素转换酶 2（ACE2）、SARS-CoV2 刺突蛋白和 SARS-CoV2 的 RNA 依赖性 RNA 聚合酶酶（RdRp）的独特结构特性。对靶分子的深入结构分析揭示了与现有药物的重要药效团特征结合的关键结合残基和结构扭曲[（7-氯-N-[5-（二乙基氨基）戊基]-4-喹啉胺（氯喹），N-[[4-（4-甲基哌嗪-1-基）苯基]甲基]-1,2-恶唑-5-甲酰胺 N-[[4-（4-甲基哌嗪-1-基）苯基]甲基]-1,2-恶唑-5-甲酰胺）（SSAA09E2），2-乙基丁基（2S）-2-[[（S）-[[（2R，3S，4R，5R）-5-[4-氨基吡咯并[2,1-f][1,2,4]三嗪-7-基]-5-氰基-3（瑞德西韦）和 6-氟-3-氧代-3,4-二氢-2-吡嗪甲酰胺（法匹拉韦）]。从这个结构信息学研究中可以明显看出，氯喹+SSAA09E2 与瑞德西韦或法匹拉韦联合使用可以在进入和复制阶段显著抑制病毒。因此，药物再利用是一种有吸引力的方法，可以缩短治疗 COVID-19 的时间和成本，我们没有足够的时间，因为整个世界都处于封锁状态，我们急需明显的治疗措施。
