Quantitative structure-activity relationships, molecular docking and molecular dynamics simulations reveal drug repurposing candidates as potent SARS-CoV-2 main protease inhibitors.

The current outbreak of COVID-19 is leading an unprecedented scientific effort focusing on targeting SARS-CoV-2 proteins critical for its viral replication. Herein, we performed high-throughput virtual screening of more than eleven thousand FDA-approved drugs using backpropagation-based artificial neural networks (q2LOO = 0.60, r2 = 0.80 and r2pred = 0.91), partial-least-square (PLS) regression (q2LOO = 0.83, r2 = 0.62 and r2pred = 0.70) and sequential minimal optimization (SMO) regression (q2LOO = 0.70, r2 = 0.80 and r2pred = 0.89). We simulated the stability of Acarbose-derived hexasaccharide, Naratriptan, Peramivir, Dihydrostreptomycin, Enviomycin, Rolitetracycline, Viomycin, Angiotensin II, Angiotensin 1-7, Angiotensinamide, Fenoterol, Zanamivir, Laninamivir and Laninamivir octanoate with 3CLpro by 100 ns and calculated binding free energy using molecular mechanics combined with Poisson-Boltzmann surface area (MM-PBSA). Our QSAR models and molecular dynamics data suggest that seven repurposed-drug candidates such as Acarbose-derived Hexasaccharide, Angiotensinamide, Dihydrostreptomycin, Enviomycin, Fenoterol, Naratriptan and Viomycin are potential SARS-CoV-2 main protease inhibitors. In addition, our QSAR models and molecular dynamics simulations revealed that His41, Asn142, Cys145, Glu166 and Gln189 are potential pharmacophoric centers for 3CLpro inhibitors. Glu166 is a potential pharmacophore for drug design and inhibitors that interact with this residue may be critical to avoid dimerization of 3CLpro. Our results will contribute to future investigations of novel chemical scaffolds and the discovery of novel hits in high-throughput screening as potential anti-SARS-CoV-2 properties.Communicated by Ramaswamy H. Sarma.

Molecular dynamics simulations of the spike trimeric ectodomain of the SARS-CoV-2 Omicron variant: structural relationships with infectivity, evasion to immune system and transmissibility.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron is currently the most prevalent SARS-CoV-2 variant worldwide. Herein, we calculated molecular dynamics simulations of the trimeric spikeWT and SpikeBA.1 for 300 ns. Our results show that SpikeBA.1 has more conformational flexibility than SpikeWT. Our principal component analysis (PCA) allowed us to observe a broader spectrum of different conformations for SpikeBA.1, mainly at N-terminal domain (NTD) and receptor-binding domain (RBD). Such increased flexibility could contribute to decreased neutralizing antibody recognition of this variant. Our molecular dynamics data show that the RBDBA.1 easily visits an up-conformational state and the prevalent D614G mutation is pivotal to explain molecular dynamics results for this variant because to lost hydrogen bonding interactions between the residue pairs K854SC/D614SC, Y837MC/D614MC, K835SC/D614SC, T859SC/D614SC. In addition, SpikeBA.1 residues near the furin cleavage site are more flexible than in SpikeWT, probably due to P681H and D614G substitutions. Finally, dynamical cross-correlation matrix (DCCM) analysis reveals that D614G and P681H may allosterically affect the cleavage site S1/S2. Conversely, S2' site may be influenced by residues located between NTD and RBD of a neighboring protomer of the SpikeWT. Such communication may be lost in SpikeBA.1, explaining the changes of the cell tropism in the viral infection. In addition, the movements of the NTDWT and NTDBA.1 may modulate the RBD conformation through allosteric effects. Taken together, our results explain how the structural aspects may explain the observed gains in infectivity, immune system evasion and transmissibility of the Omicron variant.Communicated by Ramaswamy H. Sarma.

Molecular Dynamics Analysis of Fast-Spreading Severe Acute Respiratory Syndrome Coronavirus 2 Variants and Their Effects on the Interaction with Human Angiotensin-Converting Enzyme 2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is evolving with mutations in the spike protein, especially in the receptor-binding domain (RBD). The failure of public health measures in some countries to contain the spread of the disease has given rise to novel viral variants with increased transmissibility. However, key questions about how quickly the variants can spread remain unclear. Herein, we performed a structural investigation using molecular dynamics simulations and determined dissociation constant (K D) values using surface plasmon resonance assays of three fast-spreading SARS-CoV-2 variants, alpha, beta, and gamma, as well as genetic factors in host cells that may be related to the viral infection. Our results suggest that the SARS-CoV-2 variants facilitate their entry into the host cell by moderately increased binding affinities to the human ACE2 receptor, different torsions in hACE2 mediated by RBD variants, and an increased spike exposure time to proteolytic enzymes. We also found that other host cell aspects, such as gene and isoform expression of key genes for the infection (ACE2, FURIN, and TMPRSS2), may have few contributions to the SARS-CoV-2 variant infectivity. In summary, we concluded that a combination of viral and host cell factors allows SARS-CoV-2 variants to increase their abilities to spread faster than the wild type.

Severe Acute Respiratory Syndrome Coronavirus 2 Variants of Concern: A Perspective for Emerging More Transmissible and Vaccine-Resistant Strains.

Novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) are constantly threatening global public health. With no end date, the pandemic persists with the emergence of novel variants that threaten the effectiveness of diagnostic tests and vaccines. Mutations in the Spike surface protein of the virus are regularly observed in the new variants, potentializing the emergence of novel viruses with different tropism from the current ones, which may change the severity and symptoms of the disease. Growing evidence has shown that mutations are being selected in favor of variants that are more capable of evading the action of neutralizing antibodies. In this context, the most important factor guiding the evolution of SARS-CoV-2 is its interaction with the host's immune system. Thus, as current vaccines cannot block the transmission of the virus, measures complementary to vaccination, such as the use of masks, hand hygiene, and keeping environments ventilated remain essential to delay the emergence of new variants. Importantly, in addition to the involvement of the immune system in the evolution of the virus, we highlight several chemical parameters that influence the molecular interactions between viruses and host cells during invasion and are also critical tools making novel variants more transmissible. In this review, we dissect the impacts of the Spike mutations on biological parameters such as (1) the increase in Spike binding affinity to hACE2; (2) bound time for the receptor to be cleaved by the proteases; (3) how mutations associate with the increase in RBD up-conformation state in the Spike ectodomain; (4) expansion of uncleaved Spike protein in the virion particles; (5) increment in Spike concentration per virion particles; and (6) evasion of the immune system. These factors play key roles in the fast spreading of SARS-CoV-2 variants of concern, including the Omicron.