Supervised Molecular Dynamics (SuMD) Insights into the mechanism of action of SARS-CoV-2 main protease inhibitor PF-07321332

Abstract The chemical structure of PF-07321332, the first orally available Covid-19 clinical candidate, has recently been revealed by Pfizer. No information has been provided about the interaction pattern between PF-07321332 and its biomolecular counterpart, the SARS-CoV-2 main protease (Mpro). In the present work, we exploited Supervised Molecular Dynamics (SuMD) simulations to elucidate the key features that characterise the interaction between this drug candidate and the protease, emphasising similarities and differences with other structurally related inhibitors such as Boceprevir and PF-07304814. The structural insights provided by SuMD will hopefully be able to inspire the rational discovery of other potent and selective protease inhibitors.

[1]  B. Halford.  Pfizer unveils its oral SARS-CoV-2 inhibitor , 2021 .

[2]  Maicol Bissaro,et al.  Inspecting the Mechanism of Fragment Hits Binding on SARS‐CoV‐2 Mpro by Using Supervised Molecular Dynamics (SuMD) Simulations , 2021, ChemMedChem.

[3]  M. Sturlese,et al.  A novel conformational state for SARS-CoV-2 main protease , 2021, bioRxiv.

[4]  D. Tegunov,et al.  Mechanism of SARS-CoV-2 polymerase stalling by remdesivir , 2021, Nature communications.

[5]  C. Supuran,et al.  Protease inhibitors targeting the main protease and papain-like protease of coronaviruses , 2020, Expert opinion on therapeutic patents.

[6]  A. Ganesan,et al.  Molecular dynamics and in silico mutagenesis on the reversible inhibitor-bound SARS-CoV-2 main protease complexes reveal the role of lateral pocket in enhancing the ligand affinity , 2020, Scientific Reports.

[7]  Malina A. Bakowski,et al.  Discovery of a Novel Inhibitor of Coronavirus 3CL Protease as a Clinical Candidate for the Potential Treatment of COVID-19 , 2020, bioRxiv.

[8]  L. Dodd,et al.  Remdesivir for the Treatment of Covid-19 — Final Report , 2020, The New England journal of medicine.

[9]  Bhupesh Goyal,et al.  Targeting the Dimerization of the Main Protease of Coronaviruses: A Potential Broad-Spectrum Therapeutic Strategy , 2020, ACS combinatorial science.

[10]  Hualiang Jiang,et al.  Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors , 2020, Nature.

[11]  Maicol Bissaro,et al.  Targeting the coronavirus SARS-CoV-2: computational insights into the mechanism of action of the protease inhibitors lopinavir, ritonavir and nelfinavir , 2020, Scientific Reports.

[12]  Sandro G. Viveiros Rosa,et al.  Clinical trials on drug repositioning for COVID-19 treatment , 2020, Revista panamericana de salud publica = Pan American journal of public health.

[13]  R. Hilgenfeld,et al.  Substrate specificity profiling of SARS-CoV-2 main protease enables design of activity-based probes for patient-sample imaging , 2020, bioRxiv.

[14]  Yunhui Liu,et al.  Potential interventions for novel coronavirus in China: A systematic review , 2020, Journal of medical virology.

[15]  J. Guarner.  Three Emerging Coronaviruses in Two Decades , 2020, American journal of clinical pathology.

[16]  W. C. Santos,et al.  Vector competence of Culex mosquitoes (Diptera: Culicidae) in Zika virus transmission: an integrative review , 2020, Revista panamericana de salud publica = Pan American journal of public health.

[17]  D. Heymann,et al.  COVID-19: what is next for public health? , 2020, The Lancet.

[18]  A. Wadhwani,et al.  Drug Repurposing in Antiviral Research: A Current Scenario , 2019, Journal of Young Pharmacists.

[19]  Vijay S. Pande,et al.  OpenMM 7: Rapid development of high performance algorithms for molecular dynamics , 2016, bioRxiv.

[20]  Stefano Moro,et al.  Supervised Molecular Dynamics (SuMD) as a Helpful Tool To Depict GPCR-Ligand Recognition Pathway in a Nanosecond Time Scale , 2014, J. Chem. Inf. Model..

[21]  G. Chang,et al.  Mutation of Glu-166 Blocks the Substrate-Induced Dimerization of SARS Coronavirus Main Protease , 2010, Biophysical Journal.

[22]  M J Harvey,et al.  ACEMD: Accelerating Biomolecular Dynamics in the Microsecond Time Scale. , 2009, Journal of chemical theory and computation.

[23]  Thomas Stützle,et al.  Empirical Scoring Functions for Advanced Protein-Ligand Docking with PLANTS , 2009, J. Chem. Inf. Model..

[24]  N. Shih,et al.  Challenges in modern drug discovery: a case study of boceprevir, an HCV protease inhibitor for the treatment of hepatitis C virus infection. , 2008, Accounts of chemical research.

[25]  Thomas Stützle,et al.  An ant colony optimization approach to flexible protein–ligand docking , 2007, Swarm Intelligence.

[26]  Thomas Stützle,et al.  PLANTS: Application of Ant Colony Optimization to Structure-Based Drug Design , 2006, ANTS Workshop.

[27]  Gerhard Klebe,et al.  Comparison of Automatic Three-Dimensional Model Builders Using 639 X-ray Structures , 1994, J. Chem. Inf. Comput. Sci..

[28]  W. L. Jorgensen,et al.  Comparison of simple potential functions for simulating liquid water , 1983 .

[29]  Structural bioinformatics Advance Access publication April 5, 2011 ProDy: Protein Dynamics Inferred from Theory and Experiments , 2010 .