article · Molecules
SARS-CoV-2 mutations have caused drug resistance against existing treatments and contributed to an increase in long-COVID cases. In response, drug discovery efforts focus primarily on inhibiting the mechanisms responsible for viral entry and replication to halt the viral life cycle. Current research evaluates approved medications, clinical candidates, and developmental inhibitors alongside their bioassay data and active-site binding interactions. Computational methods, including molecular docking, molecular dynamics simulations, free energy perturbation, WaterMap, and quantitative structure-activity relationship analyses, accelerate the design and discovery of these therapies when integrated with experimental testing. Identifying and addressing remaining knowledge gaps regarding mutations that alter viral entry will assist in managing resistant viral strains, alleviating long-COVID symptoms, and establishing stronger preparedness for future viral pandemics.
Ongoing mutations in the SARS-CoV-2 virus reduce the effectiveness of existing treatments, complicating the management of infections and long-COVID. Demonstrating how computational tools identify inhibitor binding mechanisms enables scientists to design targeted antiviral drugs more rapidly. This expedites discovery timelines and strengthens medical responses to emerging drug-resistant variants and future respiratory viruses.
This work supports early-stage drug design and discovery. Pharmaceutical developers and medicinal chemistry teams can apply these computational modeling strategies and binding insights to identify and optimise lead compounds targeting viral entry and replication. The material covers approved treatments alongside early pipeline candidates and in silico methodologies, indicating that direct commercial applications are situated in early-stage research and preclinical screening rather than immediate market deployment.
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The SARS-CoV-2 pandemic has significantly impacted global health, politics, medicine, finance, and society. Since 2020, various mutations have been reported, leading to drug resistance in current treatments against different SARS-CoV-2 strains and a drastic increase in cases of long-COVID. This situation underscores the urgent need to develop targeted and effective drugs to combat the spread of SARS-CoV-2 strains and their mutants, manage long-COVID symptoms and prepare for future pandemics. Currently, the treatment of SARS-CoV-2 focuses on targeting the virus's entry and replication mechanisms to disrupt its life cycle. This review examines approved drugs, clinical candidates, and inhibitors under development, along with their bioassay data, while highlighting associated challenges. It illustrates how inhibitors bind to active sites, providing insights and emphasizing the importance of in silico studies, such as molecular docking, molecular dynamics simulation, FEP+, WaterMap, and quantitative structure-activity relationship (QSAR) analyses, and their correlation with experimental studies in expediting the drug discovery process. The review aims to provide researchers with insights into the gaps that need to be addressed concerning mutations affecting viral entry and to prepare for future pandemics.
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DOI: 10.3390/molecules31162877
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