Generate, Repurpose, Validate: A Receptor-Mediated Atom-by-Atom Drug Generation for SARS-Cov-2 Spike Protein and Similarity-Mapped Drug Repurposing for COVID-19 with Rigorous Free Energy Validation Using Well-Tempered Metadynamics

Chowdhury, Rituparno; Adury, Venkata Sai Sreyas; Vijay, Amal; Singh, Reman Kumar; Mukherjee, Arnab

doi:10.26434/chemrxiv.12318311

Cited by 3 publications

(3 citation statements)

References 10 publications

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“…In other words, the binding of RBD2 to ACE2 yields about 11 kcal/mol more energy than the binding of RBD1. This ΔΔ G MD (= Δ G 1 –Δ G 2 ) is similar to an estimate (–13 kcal/mol) using metadynamics [ 41 ], but almost three times the value estimated by a coarse-grain model (–4.3 kcal/mol) in a recently published work [ 14 ], and half of the value estimated by Molecular Mechanics Generalized Born Surface Area method [ 17 ]. This disagreement may largely come from the simulated parameters (or FFs).…”

Section: Resultssupporting

confidence: 81%

Identifying key determinants and dynamics of SARS-CoV-2/ACE2 tight interaction

Ngo

Jha

2021

PLoS ONE

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SARS-CoV-2 virus, the causative agent of Covid-19, has fired up a global pandemic. The virus interacts with the human receptor angiotensin-converting enzyme 2 (ACE2) for an invasion via receptor binding domain (RBD) on its spike protein. To provide a deeper understanding of this interaction, we performed microsecond simulations of the RBD-ACE2 complex for SARS-CoV-2 and compared it with the closely related SARS-CoV discovered in 2003. We show residues in the RBD of SARS-CoV-2 that were mutated from SARS-CoV, collectively help make the RBD anchor much stronger to the N-terminal part of ACE2 than the corresponding residues on RBD of SARS-CoV. This would result in a reduced dissociation rate of SARS-CoV-2 from human receptor protein compared to SARS-CoV. The phenomenon was consistently observed in simulations beyond 500 ns and was reproducible across different force fields. Altogether, our study adds more insight into the critical dynamics of the key residues at the virus spike and human receptor binding interface and potentially aids the development of diagnostics and therapeutics to combat the pandemic efficiently.

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Section: Resultssupporting

confidence: 81%

Identifying key determinants and dynamics of SARS-CoV-2/ACE2 tight interaction

Ngo

Jha

2021

PLoS ONE

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“…A large number of antibiotics have also been tested by means of docking studies against the viral RBD. 140 − 143 Plicamycin (also known as mithramycin; see the structure in Figure 5 A) is clinically used as an anticancer agent 144 , 145 and shows a promising interaction with ACE2, in particular, at interface β, a region that is directly involved in the recognition of the viral RBD (see Figures 4 B and 5 B,C). 89 …”

Section: Sars-cov-2 Spike Glycoprotein: Structure and Dynamics Of Cormentioning

confidence: 99%

Molecular Basis of SARS-CoV-2 Infection and Rational Design of Potential Antiviral Agents: Modeling and Simulation Approaches

et al. 2020

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The emergence in late 2019 of the coronavirus SARS-CoV-2 has resulted in the breakthrough of the COVID-19 pandemic that is presently affecting a growing number of countries. The development of the pandemic has also prompted an unprecedented effort of the scientific community to understand the molecular bases of the virus infection and to propose rational drug design strategies able to alleviate the serious COVID-19 morbidity. In this context, a strong synergy between the structural biophysics and molecular modeling and simulation communities has emerged, resolving at the atomistic level the crucial protein apparatus of the virus and revealing the dynamic aspects of key viral processes. In this Review, we focus on how in silico studies have contributed to the understanding of the SARS-CoV-2 infection mechanism and the proposal of novel and original agents to inhibit the viral key functioning. This Review deals with the SARS-CoV-2 spike protein, including the mode of action that this structural protein uses to entry human cells, as well as with nonstructural viral proteins, focusing the attention on the most studied proteases and also proposing alternative mechanisms involving some of its domains, such as the SARS unique domain. We demonstrate that molecular modeling and simulation represent an effective approach to gather information on key biological processes and thus guide rational molecular design strategies.

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“…Large scale screening of therapeutic molecules and antibodies are underway, aiming to target the spike protein and consequently to prevent infection. Most of the experimental [11][12][13][14] and computational [15][16][17] efforts for inhibitor design focus on the receptor binding domain (RBD), despite the fact that this region is highly mutation-prone 18 and can cause resistance to therapeutics. For example, the mutations in the RBD observed in the emerging viral lineage in South Africa resulted in up to a ten-fold reduction in the neutralization capacity of conventional antibody therapy.…”

Section: Introductionmentioning

confidence: 99%

Distant Residues Modulate Conformational Opening in SARS-CoV-2 Spike Protein

Ray

Andricioaei

2020

Preprint

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Infection by SARS-CoV-2 involves the attachment of the receptor binding domain (RBD) of its spike proteins to the ACE2 receptors on the peripheral membrane of host cells. Binding is initiated by a down to up conformational change in the spike protein, an opening which presents the RBD to the receptor. To date, computational and experimental studies for therapeutics have concentrated, for good reason, on the RBD. However, the RBD region is highly prone to mutations, and therefore will possibly arise drug resistance. In contrast, we here focus on the correlations between the RBD and residues distant to it in the spike protein. We thereby provide a deeper understanding of the role of distant residues in the molecular mechanism of infection. Predictions of key mutations in distant allosteric binding sites are provided, with implications for therapeutics. Identifying these emerging mutants can also go a long way towards pre-designing vaccines for future outbreaks. The model we use, based on time-independent component analysis (tICA) and protein graph connectivity network, is able to identify multiple residues that exhibit long-distance coupling with the RBD opening. Mutation on these residues can lead to new strains of coronavirus with different degrees of transmissibility and virulence. The most ubiquitous D614G mutation and the A570D mutation of the highly contagious UK SARS-CoV-2 variant are predicted ab-initio from our model. Conversely, broad spectrum therapeutics like drugs and monoclonal antibodies can be generated targeting these key distant but conserved regions of the spike protein.Significance statementThe novel coronavirus (SARS-CoV-2) pandemic resulted in the largest economic and public health crises in recent times. Significant drug design effort, against SARS-CoV-2, is focused on the receptor binding domain (RBD) of the spike protein, although this region is prone to mutations causing therapeutic resistance. We applied deep data analysis methods on all-atom molecular dynamics simulations to identify key non-RBD residues that play a crucial role in spike-receptor binding and infection. Because the non-RBD residues are typically conserved across multiple coronaviruses, they can not only be targeted by broad spectrum antibodies and drugs against existing strains, but can also offer predictive insights into how to design adaptable antiviral therapeutic framework against spike of strains that might appear during future epidemics.

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Generate, Repurpose, Validate: A Receptor-Mediated Atom-by-Atom Drug Generation for SARS-Cov-2 Spike Protein and Similarity-Mapped Drug Repurposing for COVID-19 with Rigorous Free Energy Validation Using Well-Tempered Metadynamics

Cited by 3 publications

References 10 publications

Identifying key determinants and dynamics of SARS-CoV-2/ACE2 tight interaction

Identifying key determinants and dynamics of SARS-CoV-2/ACE2 tight interaction

Molecular Basis of SARS-CoV-2 Infection and Rational Design of Potential Antiviral Agents: Modeling and Simulation Approaches

Distant Residues Modulate Conformational Opening in SARS-CoV-2 Spike Protein

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