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An integrated understanding of the evolutionary and structural features of the SARS-CoV-2 spike receptor binding domain (RBD).
Sanyal, Dwipanjan; Banerjee, Suharto; Bej, Aritra; Chowdhury, Vaidehi Roy; Uversky, Vladimir N; Chowdhury, Sourav; Chattopadhyay, Krishnananda.
  • Sanyal D; Protein Folding and Dynamics Group, Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata 700 032, India.
  • Banerjee S; Protein Folding and Dynamics Group, Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata 700 032, India.
  • Bej A; Protein Folding and Dynamics Group, Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata 700 032, India.
  • Chowdhury VR; Protein Folding and Dynamics Group, Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata 700 032, India.
  • Uversky VN; Department of Molecular Medicine and USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA; Laboratory of New Methods in Biology, Institute for Biological Instrumentation of the Russian Academy of Sciences, Federal Research Center "P
  • Chowdhury S; Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address: sourav_chowdhury@fas.harvard.edu.
  • Chattopadhyay K; Protein Folding and Dynamics Group, Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, Kolkata 700 032, India. Electronic address: krish@iicb.res.in.
Int J Biol Macromol ; 217: 492-505, 2022 Sep 30.
Article in English | MEDLINE | ID: covidwho-1926499
ABSTRACT
Conventional drug development strategies typically use pocket in protein structures as drug-target sites. They overlook the plausible effects of protein evolvability and resistant mutations on protein structure which in turn may impair protein-drug interaction. In this study, we used an integrated evolution and structure guided strategy to develop potential evolutionary-escape resistant therapeutics using receptor binding domain (RBD) of SARS-CoV-2 spike-protein/S-protein as a model. Deploying an ensemble of sequence space exploratory tools including co-evolutionary analysis and deep mutational scans we provide a quantitative insight into the evolutionarily constrained subspace of the RBD sequence-space. Guided by molecular simulation and structure network analysis we highlight regions inside the RBD, which are critical for providing structural integrity and conformational flexibility. Using fuzzy C-means clustering we combined evolutionary and structural features of RBD and identified a critical region. Subsequently, we used computational drug screening using a library of 1615 small molecules and identified one lead molecule, which is expected to target the identified region, critical for evolvability and structural stability of RBD. This integrated evolution-structure guided strategy to develop evolutionary-escape resistant lead molecules have potential general applications beyond SARS-CoV-2.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Limits: Humans Language: English Journal: Int J Biol Macromol Year: 2022 Document Type: Article Affiliation country: J.ijbiomac.2022.07.022

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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Limits: Humans Language: English Journal: Int J Biol Macromol Year: 2022 Document Type: Article Affiliation country: J.ijbiomac.2022.07.022