ABSTRACT
BACKGROUND: To combat the global health issue caused by SARS-CoV2, scientists are attempting various therapeutic approaches towards drug discovery including computational biology and drug-repurposing. Recent studies have highlighted the conserved nature of RNA-dependent RNA polymerase (RdRp) of coronaviruses affecting human, bat and animals. In this study attempts have been made to identify the potential inhibitors of RdRp by utilizing molecular docking and MD simulation studies. METHOD(S): Systematic structure-based screening of chemical compounds from public libraries was performed to identify the potential lead molecules inhibiting RdRp. This structure driven clustering of compounds is based on decision tree model generated by combining two properties: 1) shape descriptors;and 2) critical number of multiple bonds. The enabled screening of potential chemical compounds was subjected to molecular docking followed by molecular dynamics simulation studies. RESULT(S): The results revealed that the stability of protein-drug complex structure was in the order of RdRp-Oxoglaucine >RdRp-Flutroline >RdRp-Brucine complex. CONCLUSION(S): This study identifies Oxoglaucine, Brucine and Flutroline as prospective inhibiting agents of SARS-CoV-2 RdRp and further warrants for experimental validation. Copyright © 2022 EDIZIONI MINERVA MEDICA.
ABSTRACT
BACKGROUND: Recurrent outbreaks of respiratory viruses like SARS-CoV (severe acute respiratory syndrome-coronavirus, 2002), MERS (Middle East respiratory syndrome, 2012) including the ongoing SARS-CoV-2 (2019) pandemic warrants for a single-broad-spectrum vaccine against these respiratory viruses. METHOD(S): In the present study, phylogenetic analysis followed by in-silico identification of vaccine candidates for SARS, MERS and SARS-CoV-2 was performed by exploiting T-cell and B-cell mapping to ascertain the best possible epitopes for effector humoral- and cell-mediated immune response. Further, population-coverage analysis of the identified epitopes followed by the designing of chimera of epitope-based vaccine was done using linkers and adjuvants. Docking study was done to appraise the interaction of the proposed vaccine with ACE2 (angiotensin converting enzyme-2) receptor (SARS and SARS-CoV-2) and HLA-B7 (human leukocyte antigen) receptor (MERS). The stability of the vaccine chimera was confirmed by molecular dynamics performed for 20 ns;this was followed by codon optimization and in-silico cloning. RESULT(S): Phylogenetic analysis revealed similarity among SARS-CoV-2, SARS-CoV and bat SARS-like coronavirus. Both, SARS-CoV and SARS-CoV-2 were from different class than MERS, whereas SARS-CoV-2 showed more relatedness with Bat SARS-like coronaviruses. The most suitable epitopes found were LSFELLNAPATVCGP (SARS), LVTLAILTALRLCAY (SARS-CoV-2) and YTSAFNWLL (MERS) with nearly 98% population coverage. Molecular docking followed by simulation studies revealed high number of hydrogen bonds, stable RMSD values and acceptable RMSF flexibility scores, indicating stable interactions of the vaccine with ACE2 and MHC receptors (Major histocompat-ibility complex). Expression of the designed multiepitope vaccine in E. coli (Escherichia coli) expression system was confirmed by in-silico cloning/codon optimization. CONCLUSION(S): Further, in-vitro and in-vivo experimental validation studies are required to endorse our current findings. Copyright © 2022 EDIZIONI MINERVA MEDICA.