Probing conserved catalytic domains in RNA polymerases of severe acute respiratory syndrome coronavirus, human metapneumovirus and respiratory syncytial virus for computational insights

The alarming rise in lower-respiratory tract infections (LRTIs) post COVID-19 pandemic is a serious global healthcare concern that necessitates urgent therapeutic solutions. In this study, we have concentrated on RNA-dependent RNA-polymerase (RdRp), which can serve as a promising target for drug development against LRTI-causing viruses. To achieve this, we aim to take the study beyond evolutionary validation between the viruses and examine conserved residues to encourage structure-based drug design. We have retrieved whole genomes of viruses causing LRTI ( n = 345) viz., influenza, Rhinovirus, respiratory syncytial virus (RSV), human metapneumovirus (HMPV), and severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV and SARS-CoV-2). Interestingly, local alignment of RNA polymerase protein sequences of LRTI causing viruses reveal coherence in the catalytic domains indicating the presence of conserved motifs in SARS-CoV-2, HMPV, RSV (∼50 to 80% similarities). These similarities encouraged us to examine anti-RSV anti-viral peptides (AVPs) against the RNA-polymerases of HMPV and SARS-CoV-2. The clustering approach and dynamics simulations further aided the identification of an anti-RSV AVP-candidate (P15) showing higher affinity (Energy < −200 kcal/mol). These results were further validated through MM-PBSA analysis, highlighting favorable binding free energetics. Our study reveals conserved stretches in the catalytic domain and was considered to be important drug targets in RSV, SARS-CoV-2, and HMPV. Despite of global genomic dissimilarities, the present study stands out by depicting the relevance of local similarities and conserved residues in the putative targets for drug designing. These findings strongly encourage further experimental validations and genomic excavations for therapeutic breakthroughs against emerging viruses.