How helpful were molecular dynamics simulations in shaping our understanding of SARS-CoV-2 spike protein dynamics?

The SARS-CoV-2 spike protein (S) represents an important viral component that is required for successful viral infection in humans owing to its essential role in recognition of and entry to host cells. The spike is also an appealing target for drug designers who develop vaccines and antivirals. This article is important as it summarizes how molecular simulations successfully shaped our understanding of spike conformational behavior and its role in viral infection. MD simulations found that the higher affinity of SARS-CoV-2-S to ACE2 is linked to its unique residues that add extra electrostatic and van der Waal interactions in comparison to the SARS-CoV S. This illustrates the spread potential of the pandemic SARS-CoV-2 relative to the epidemic SARS-CoV. Different mutations at the S-ACE2 interface, which is believed to increase the transmission of the new variants, affected the behavior and binding interactions in different simulations. The contributions of glycans to the opening of S were revealed via simulations. The immune evasion of S was linked to the spatial distribution of glycans. This help the virus to escape the immune system recognition. This article is important as it summarizes how molecular simulations successfully shaped our understanding of spike conformational behavior and its role in viral infection. This will pave the way to us preparing for the next pandemic as the computational tools are tailored to help fight new challenges.

The discovery of novel antivirals for the treatment of mpox: is drug repurposing the answer?

INTRODUCTION: Drugs that have demonstrated good activity against any member of the Orthopoxvirus genus are good candidates for repurposing studies against the mpox virus (MPXV). The conserved biology of poxviruses has proven beneficial from a clinical virology perspective. Evolutionarily conserved proteins tend to function in a highly similar way. Indeed, the smallpox vaccine was found to be 85% effective in protecting humans from mpox virus infection. Similarly, tecovirimat, the drug of choice for smallpox infections, was recently repurposed as a treatment option for mpox cases in Europe. AREA COVERED: This review article focuses on drug repurposing strategies to combat the newly emerged MPXV outbreak. The viral and host cell protein targets are challenged with a bunch of drugs and drug-like molecules in silico, in vitro, and in vivo. Some drugs show promising results and can be repurposed to eradicate MPXV infection. The authors also highlight potential limitations and provide their expert perspectives. EXPERT OPINION: Overall, it is clear that we cannot solely rely on the conventional drug discovery pipeline to find new treatments, despite advances in computational and experimental advances in the last few decades. Drug repurposing has successfully identified good candidate drugs against MPXV as it is one of the Orthopoxvirus genus family. Tecovirimat, brincidofovir, and cidofovir have shown promising results in preventing virus propagation. Consequently, drug repurposing represents an important strategy for the fast identification of new therapeutic options.

Novel inhibitors against wild-type and mutated HCV NS3 serine protease: an in silico study.

In 2011, the FDA approved boceprevir as a hepatitis C virus (HCV) NS3 serine protease inhibitor. The sustained virological response rate for treatment with this approved compound is considerably low. Patients have not responded as much as expected to boceprevir therapy. In this in silico study, modified boceprevir compounds are suggested and tested on wild-type HCV NS3 protease and 19 mutated HCV NS3 proteases using molecular docking. Results reveal the superiority of two of the proposed modified compounds to boceprevir. One of which appears to be more potent than boceprevir itself concerning activity against wild-type NS3 and most of the examined mutated NS3 proteases.

A comparative study of the efficiency of HCV NS3/4A protease drugs against different HCV genotypes using in silico approaches.

AIMS: To investigate the efficacy of Direct Acting Antivirals (DAAs) in the treatment of different Hepatitis C Virus (HCV) genotypes. MAIN METHODS: Homology modeling is used to predict the 3D structures of different genotypes while molecular docking is employed to predict genotype - drug interactions (Binding Mode) and binding free energy (Docking Score). KEY FINDINGS: Simeprevir (TMC435) and to a lesser degree MK6325 are the best drugs among the studied drugs. The predicted affinity of drugs against genotype 1a is always better than other genotypes. P2-P4 macrocyclic drugs show better performance against genotypes 2, 3 and 5. Macrocyclic drugs are better than linear drugs. SIGNIFICANCE: HCV is one of the major health problems worldwide. Until the discovery of DAAs, HCV treatment faced many failures. DAAs target key functional machines of the virus life cycle and shut it down. NS3/4A protease is an important target and several drugs have been designed to inhibit its functions. There are several NS3/4A protease drugs approved by Food and Drug Administration (FDA). Unfortunately, the virus exhibits resistance against these drugs. This study is significant in elucidating that no one drug is able to treat different genotypes with the same efficiency. Therefore, treatment should be prescribed based on the HCV genotype.

Molecular docking investigation of the binding interactions of macrocyclic inhibitors with HCV NS3 protease and its mutants (R155K, D168A and A156V).

Hepatitis C Virus (HCV) non-structural protein 3 (NS3) protease drug resistance poses serious challenges on the design of an effective treatment. Substrate Envelope Hypothesis, "the substrates of HCV NS3/4A protease have a consensus volume inside the active site called substrate envelope" is used to design potent and specific drugs to overcome this problem. Using molecular docking, we studied the binding interaction of the different inhibitors and protein and evaluated the effect of three different mutations (R155K, D168A and A156V) on the binding of inhibitors. P2-P4 macrocycles of 5A/5B and modified 5A/5B hexapeptide sequences have the best scores against the wild-type protein -204.506 and -206.823 kcal/mole, respectively. Also, charged P2-P4 macrocycles of 3/4A and 4A/4B hexapeptide sequences have low scores with the wild-type protein -200.467 and -203.186 kcal/mole, respectively. R155K mutation greatly affects the conformation of the compounds inside the active site. It inverts its orientations, and this is because the large and free side chain of K155 which restricts the conformation of the large P2-P4 macrocycle. The conformation of charged P2-P4 macrocycle of 3/4A hexapeptide sequence in wild-type, A156V and D168A proteins is nearly equal; while that of charged P2-P4 macrocycle of 4A/4B hexapeptide sequence is different. Nevertheless, these compounds have a slight increase of Van der Waals volume compared to that of substrates, they are potent against mutations and have good scores. Therefore, the suggested drugs can be used as an effective treatment solving HCV NS3/4A protease drug resistance problem.

QSAR analysis and molecular docking simulation of suggested peptidomimetic NS3 protease inhibitors.

Based on the N-terminal hexapeptide product of hydrolysis (EDVVCC) at HCV NS5A/5B junction, three modified groups of compounds are built. The first group contains linear peptides while the second and third groups contain P1-P3 and P2-P4 macrocyclic structures, respectively. Quantitative Structure Activity Relationship (QSAR) characterization and docking simulations are performed in order to investigate the potential of these compounds as HCV NS3/4A protease inhibitors. Based on the QSAR properties, the three most stable compounds due to their lowest total energy are P1-P3 and P2-P4 macrocycles of azahexapeptide sequence (DDIVP vinyl amino cyclopropane) and P2-P4 macrocycle of azahexapeptide sequence (DDIVP norvaline). They also have high surface area, solvent accessible surface area, volume, molar refractivity and polarizabilty. They have moderately low dipole moment and good log P values, as well. The docking scores of the best two P2-P4 macrocycles are just acceptable. The two compounds 5A/5B hexapeptide sequence (DDIVP vinyl amino cyclopropane) and P2-P4 macrocycle of azapentapeptide sequence (DIVP vinyl amino cyclopropane) yielded the best docking scores.