Mechanistic insights of key host proteins and potential repurposed inhibitors regulating SARS‐CoV‐2 pathway. Issue 18 (10th May 2022)

• Record Type: Journal Article
• Authors: Pramanik, Debabrata; Pawar, Aiswarya B.; Roy, Sudip; Singh, Jayant Kumar
• Is Part Of: Journal of computational chemistry. Volume 43:Issue 18(2022)
• Page Start: 1237
• Page End: 1250
• Publication Date: 2022-05-10
• Subjects: dissociation pathways -- host proteins -- inhibitors -- metadynamics -- molecular dynamics; Chemistry -- Data processing -- Periodicals; 542.85
• DOI: 10.1002/jcc.26888
• Languages: English
• ISSNs: 0192-8651

Abstract

Abstract: The emergence of pandemic situations originated from severe acute respiratory syndrome (SARS)‐CoV‐2 and its new variants created worldwide medical emergencies. Due to the non‐availability of efficient drugs and vaccines at these emergency hours, repurposing existing drugs can effectively treat patients critically infected by SARS‐CoV‐2. Finding a suitable repurposing drug with inhibitory efficacy to a host‐protein is challenging. A detailed mechanistic understanding of the kinetics, (dis)association pathways, key protein residues facilitating the entry–exit of the drugs with targets are fundamental in selecting these repurposed drugs. Keeping this target as the goal of the paper, the potential repurposing drugs, Nafamostat, Camostat, Silmitasertib, Valproic acid, and Zotatifin with host‐proteins HDAC2, CSK22, eIF4E2 are studied to elucidate energetics, kinetics, and dissociation pathways. From an ensemble of independent simulations, we observed the presence of single or multiple dissociation pathways with varying host‐proteins‐drug systems and quantitatively estimated the probability of unbinding through these specific pathways. We also explored the crucial gateway residues facilitating these dissociation mechanisms. Interestingly, the residues we obtained for HDAC2 and CSK22 are also involved in the catalytic activity. Our results demonstrate how these potential drugs interact with the host machinery and the specific target residues, showing involvement in the mechanism. Most of these drugs are in the preclinical phase, and some are already being used to treat severe COVID‐19 patients. Hence, the mechanistic insight presented in this study is envisaged to support further findings of clinical studies and eventually develop efficient inhibitors to treat SARS‐CoV‐2. Abstract : Repurposing existing drugs can effectively treat patients critically infected by SARS‐CoV‐2. Lack of detailed mechanistic understanding is a challenge. Employing molecular dynamics and enhanced sampling techniques, we explored dominant pathways for host‐proteins‐inhibitors essential in viral mechanism. Our results demonstrate the interaction mechanism of these important repurposing drugs with the host machinery and the involvement of the key protein residues in the dissociation mechanism.