Timoteo Delgado-Maldonado, Luis D Gonzalez-Morales, Gilberto Vargas-Salas, Guadalupe Rojas-Verde, Eyra Ortíz-Pérez, Alma D Paz-Gonzalez, Gildardo Rivera
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引用次数: 0
Abstract
Background: To date, COVID-19 has caused over 772 million cases, with approximately 7 million deaths, according to the World Health Organization. Therefore, there is a need to develop new drugs to address the challenges posed by this disease.
Objective: To propose new antiviral agents based on the natural product curcumin as potential protein-protein interaction inhibitors between the SARS-CoV-2 spike receptor binding domain (RBD) and the ACE2 receptor.
Methods: A curcumin-based virtual screening was performed (Tanimoto coefficient= 0.9), and molecular docking analysis were carried out using the RBD as a receptor. Molecular dynamics (MD) using GROMACS were conducted for 120 ns. The SwissADME server was used to predict pharmacokinetics. To validate predictions, an in vitro enzyme assay measuring the relative inhibition of the interaction between the RBD and the ACE2 receptor was performed.
Results: More than 1300 ligands were evaluated through molecular docking. The docking results were analyzed, and the ligands were classified according to their score and profile of interactions with residues of the RBD of the SARS-CoV-2 S glycoprotein. The top ten with the best scores and interactions were selected to verify the commercial availability. The lead compound Cu-1 demonstrated significant interactions with the RBD and stability in MD simulations, was acquired and evaluated in vitro. Compound Cu-1 inhibited 36 ± 0.7 % the interaction between the SARSCoV- 2 spike and the ACE2 receptor. In addition, Cu-1 was shown to have an acceptable druglikeness and pharmacokinetic profile.
Conclusion: Curcumin provides a scaffold for identifying novel compounds with potential antiviral activity. Further studies on compound Cu-1 could yield on optimizing its structure to increase activity targeting the RBD of the S glycoprotein.
期刊介绍:
Aims & Scope
Medicinal Chemistry a peer-reviewed journal, aims to cover all the latest outstanding developments in medicinal chemistry and rational drug design. The journal publishes original research, mini-review articles and guest edited thematic issues covering recent research and developments in the field. Articles are published rapidly by taking full advantage of Internet technology for both the submission and peer review of manuscripts. Medicinal Chemistry is an essential journal for all involved in drug design and discovery.