Mani Mohan, Vellusamy Mahesh, Rathinavel Thirumalaisamy, Vadivel Pullar, Dauchez Manuel, Khan Riaz, Aroulmoji Vincent
Centre for Research & Development, Mahendra Engineering College (Autonomous), Mallasamudram, Namakkal (Dt.), Tamil Nadu, India.
Universite ́ de Reims Champagne Ardenne, CNRS, MEDyC UMR 7369, Reims, France.
J Biomol Struct Dyn. 2024 Mar 27:1-15. doi: 10.1080/07391102.2024.2328745.
The impact of COVID-19 urges scientists to develop targeted drug delivery to manage Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) viral infections with a fast recovery rate. The aim of the study is to develop Hyaluronic Acid (HA) drug conjugates of viral drugs to target two important enzymes (Mpro and PLpro) of SARS-CoV-2. Three antiviral drugs, namely Dexamethasone (DEX), Favipiravir (FAV), and Remdesivir (REM), were chosen for HA conjugation due to their reactive functional groups. Free forms of drugs (DEX, FAV, REM) and HA drug conjugates (HA-DEX, HA-FAV, HA-REM, HA-RHA, HA-RHE) were validated against Mpro (PDB ID 6LU7) and PLpro (PDB 7LLZ), which play an essential role in the replication and reproduction of the SARS-CoV-2 virus. The results of the present study revealed that HA-drug conjugates possess higher binding affinity and the best docking score towards the Mpro and PLpro target proteins of SARS-CoV-2 than their free forms of drugs. ADMET screening resulted that HA-drug conjugates exhibited better pharmacokinetic profiles than their pure forms of drugs. Further, molecular dynamic simulation studies, essential dynamics and free energy landscape analyses show that HA antiviral drug conjugates possess good trajectories and energy status, with the PLpro target protein (PDB 7LLZ) of SARS-CoV-2 through long-distance (500 ns) simulation screening. The research work recorded the best drug candidate for Cell-Targeted Drug Delivery (CTDD) for SARS-CoV-2-infected cells through hyaluronic acid conjugates of antiviral drugs.
新型冠状病毒肺炎（COVID-19）的影响促使科学家们开发靶向给药系统，以快速恢复的速率来控制严重急性呼吸综合征冠状病毒2（SARS-CoV-2）病毒感染。本研究的目的是开发病毒药物的透明质酸（HA）药物偶联物，以靶向SARS-CoV-2的两种重要酶（Mpro和PLpro）。由于三种抗病毒药物地塞米松（DEX）、法匹拉韦（FAV）和瑞德西韦（REM）具有反应性官能团，因此被选择用于与HA偶联。针对在SARS-CoV-2病毒复制和繁殖中起重要作用的Mpro（PDB ID 6LU7）和PLpro（PDB 7LLZ），对游离形式的药物（DEX、FAV、REM）和HA药物偶联物（HA-DEX、HA-FAV、HA-REM、HA-RHA、HA-RHE）进行了验证。本研究结果表明，HA药物偶联物对SARS-CoV-2的Mpro和PLpro靶蛋白的结合亲和力高于其游离形式的药物，且对接分数最佳。ADMET筛选结果表明，HA药物偶联物的药代动力学特征优于其纯药物形式。此外，分子动力学模拟研究、主成分动力学和自由能景观分析表明，通过长距离（500 ns）模拟筛选，HA抗病毒药物偶联物与SARS-CoV-2的PLpro靶蛋白（PDB 7LLZ）具有良好的轨迹和能量状态。该研究工作通过抗病毒药物的透明质酸偶联物，记录了针对SARS-CoV-2感染细胞的细胞靶向给药（CTDD）的最佳候选药物。
