The current outbreak of highly transmissible fatal pneumonia in human caused by Coronavirus Disease-2019 (Covid-19) is spreading alarmingly and number of deaths due to infection is increasing aggressively every day and therefore we are in urgent need to find a potent drug. Conventional time-consuming drug development methods can be accelerated by reliable computational approaches in screening of compounds from chemical space or by drug repurposing or by identifying the phytochemicals which can be immediately used without drug-trials for evaluating its safety and efficacy. Many plant products were used as effective drugs in traditional Indian and Chinese medicine. Thepresent study aims to exploit molecular docking, combined molecular dynamics and MM-GBSA based free energy calculations approaches to evaluatethe potency of four selected phytochemicals namely andrographolide (AGP1), 14-deoxy 11,12-didehydro andrographolide (AGP2), neoandrographolide (AGP3) and 14-deoxy andrographolide (AGP4) from Andrographispaniculataagainst the four key targets in Covid-19 including three non-structural proteins (3 L main protease (3CLpro), Papain-like proteinase (PLpro) and RNA-directed RNA polymerase (RdRp)) and a structural protein (spike protein (S)) which are responsible for viral replication, transcription and host cell recognition. The therapeutic potential of the selected phytochemicals against Covid-19 were also evaluated in comparison with a few commercially drugs which are under consideration for Covid-19 treatment. Our results suggested that the compound AGP3 can be effective during both initial and matured state of Covid-19 viral infection and has a multi-targeting character similar to the drug cocktails used in HIV.  We have also evidenced its microscopic mechanism through rational computational modelling. Among the four phytochemicals, AGP3 has shown promising binding affinity towards all the four targets namely, 3CLpro, PLpro, RdRp and Spike protein with precise binding to the catalytic site required for inhibiting the targets in a therapeutic way. The residue-wise contributions of binding free energies has shown that in the case of 3CLpro and RdRp there is still scope for the improvement through the chemical modification of the ligand.  The binding free energy data also suggested that AGP3 could be used as a cost-effective drug-analog for treating covid-19 infection in developing countries.

Keywords: SARS-CoV-2; Andrographispaniculata; andrographolide; neoandrographolide; RNA directed RNA polymerase; Spike Protein.