RESUMEN
The Replication Associated Proteins (RAP-1 and RAP-2) encoded by CMV ORF 1a and ORF 2a are required for the different stages of the viral replication cycle; being multi-functional, they are good inhibitory targets for anti-CMV compounds. As a new perspective for sustainable crop improvement, we investigated the natural plant-based antimicrobial phytoalexins for their anti-CMV potential. Here, we modeled and predicted the functional domains of RAP-1 and RAP-2, docked with a ligand library comprising 128 phytoalexins reported with broad-spectrum activity, determined their binding energies (BEs), molecular interactions, and inhibition constant (Ki), and compared with the reference plant antiviral compounds ribavirin, ningnanmycin, and benzothiadiazole (BTH). Further, the change in Gibb's free energy of binding (ΔG) and the per residue contribution of the selected top-scored ligand molecules was assessed by the prime MM-GBSA approach. Our results revealed RAP-1 as a discontinuous two-domain and RAP-2 as a multi-domain protein. The compounds glyceollidin (9.8 kcal/mol) and moracin D (7.8 kcal/mol) topped the list for RAP-1 and RAP-2 protein targets respectively and also, the lead molecules had energetically more favorable and comparative ΔG values than the top-scored plant antiviral agent ningnanmycin. The evaluation of in vitro toxicity and agrochemical-like properties showed the least toxicity of these anti-CMV compounds. Taken together, our results provide new insights in understanding the inhibitory effects of phytoalexins towards the RAP proteins and could be employed as new promising anti-CMV candidate compounds for their application in agriculture as biopesticides to combat the CMV disease incidence.Communicated by Ramaswamy H. Sarma.
