In silico validation of hyaluronic acid – drug conjugates based targeted drug delivery for the treatment of COVID-19

Abstract

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. Communicated by Ramaswamy H. Sarma