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The COVID-19 pandemic has emerged as a global medico-socio-economic disaster. Given the lack of effective therapeutics against SARS-CoV-2, scientists are racing to disseminate suggestions for rapidly deployable therapeutic options, including drug repurposing and repositioning strategies. Molecular dynamics (MD) simulations have provided the opportunity to make rational scientific breakthroughs in a time of crisis. Advancements in these technologies in recent years have become an indispensable tool for scientists studying protein structure, function, dynamics, interactions, and drug discovery. Integrating the structural data obtained from high-resolution methods with MD simulations has helped in comprehending the process of infection and pathogenesis, as well as the SARS-CoV-2 maturation in host cells, in a short duration of time. It has also guided us to identify and prioritize drug targets and new chemical entities, and to repurpose drugs. Here, we discuss how MD simulation has been explored by the scientific community to accelerate and guide translational research on SARS-CoV-2 in the past year. We have also considered future research directions for researchers, where MD simulations can help fill the existing gaps in COVID-19 research.

The H1N1 influenza virus causes a severe disease that affects the human respiratory tract leading to millions of deaths every year. At present, certain vaccines and few drugs are used to control the virus during seasonal outbreaks. However, high mutation rates and genetic reassortment make it challenging to prevent and mitigate outbreaks, leading to pandemics. Thus, alternate therapies are required for its management and control. Here, we report that a bacterial protein, azurin, and its peptide derivatives p18 and p28 target critical proteins of the influenza virus in an effective manner. The molecular docking studies show that the p28 peptide could target C-PB1, NS1-ED, PB2-CBD, PB2-RBD, NP, and PA proteins. These complexes were further subjected to the simulation of molecular dynamics and binding free energy calculations. The data indicate that p28 has an unusually high affinity and forms stable complexes with the viral proteins C-PB1, PB2-CBD, PB2-RBD, and NP. We suggest that the azurin derivative p28 peptide can act as an anti-influenza agent as it can bind to multiple targets and neutralize the virus. Additional experimental studies need to be conducted to evaluate its safety and efficacy as an anti-H1N1 molecule., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG part of Springer Nature.)

Fasciola gigantica is the causative organism of fascioliasis and is responsible for major economic losses in livestock production globally. F. gigantica thioredoxin1 (FgTrx1) is an important redox-active enzyme involved in maintaining the redox homeostasis in the cell. To identify a potential anti-fasciolid compound, we conducted a structure-based virtual screening of natural compounds from the ZINC database (n = 1,67,740) against the FgTrx1 structure. The ligands were docked against FgTrx1 and 309 ligands were found to have better docking score. These compounds were evaluated for Lipinski and ADMET prediction, and 30 compounds were found to fit well for re-docking studies. After refinement by molecular docking and drug-likeness analysis, three potential inhibitors (ZINC15970091, ZINC9312362, and ZINC9312661) were identified. These three ligands were further subjected to molecular dynamics simulation (MDS) to compare the dynamics and stability of the protein structure after binding of the ligands. The binding free energy analyses were calculated to determine the intermolecular interactions. The results suggested that the two compounds had a binding free energy of -82.237, and -109.52 kJ.mol -1 for compounds with IDs ZINC9312362 and ZINC9312661, respectively. These predicted compounds displayed considerable pharmacological and structural properties to be drug candidates. We concluded that these two compounds could be potential drug candidates to fight against F. gigantica parasites.

Mycobacterium tuberculosis is the etiological agent of tuberculosis in humans and is responsible for more than two million deaths annually. M. tuberculosis isocitrate lyase (MtbICL) catalyzes the first step in the glyoxylate cycle, plays a pivotal role in the persistence of M. tuberculosis, which acts as a potential target for an anti-tubercular drug. To identify the potential anti-tuberculosis compound, we conducted a structure-based virtual screening of natural compounds from the ZINC database (n = 1,67,748) against the MtbICL structure. The ligands were docked against MtbICL in three sequential docking modes that resulted in 340 ligands having better docking score. These compounds were evaluated for Lipinski and ADMET prediction, and 27 compounds were found to fit well with re-docking studies. After refinement by molecular docking and drug-likeness analyses, three potential inhibitors (ZINC1306071, ZINC2111081, and ZINC2134917) were identified. These three ligands and the reference compounds were further subjected to molecular dynamics simulation and binding energy analyses to compare the dynamic structure of protein after ligand binding and the stability of the MtbICL and bound complexes. The binding free energy analyses were calculated to validate and capture the intermolecular interactions. The results suggested that the three compounds had a negative binding energy with -96.462, -143.549, and -122.526 kJ mol -1 for compounds with IDs ZINC1306071, ZINC2111081, and ZINC2134917, respectively. These lead compounds displayed substantial pharmacological and structural properties to be drug candidates. We concluded that ZINC2111081 has a great potential to inhibit MtbICL and would add to the drug discovery process against tuberculosis.

Mycobacterium tuberculosis isocitrate lyase (MtbICL) is a key enzyme of the glyoxylate cycle that catalyzes the cleavage of isocitrate to succinate and glyoxylate and is a potential antituberculosis drug target. The aim of this research was to explore the structural alterations induced by L418A point mutation that caused the loss of enzyme activity. In-depth structural analyses were carried out for understanding the influence of L418A mutation using techniques, viz. molecular dynamics, principal component analysis, time-dependent secondary structure, residue interaction network and molecular docking. Since L418A mutation site is structurally far from the active site, it cannot influence the binding of the substrate directly. Our results showed that collective motions, residual mobility, and flexibility of the enzyme increased upon mutation. The mutated residue changed the global conformational dynamics of the system along with the residue-residue interaction network, leading to a loss of the enzyme activity. The docking results suggest that L418A mutation influenced the binding interactions of the substrate with several residues in the active site of MtbICL. This study provides information on the structural dynamics of MtbICL and highlights the importance of residue level interactions in the protein. Thus, our results may provide significant guidance to the scientific community engaged in designing potent inhibitors targeting MtbICL., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Glutathione S-transferases (GSTs) are multifunctional enzymes that play major roles in a wide range of biological processes, including cellular detoxification, biosynthesis, metabolism, and transport. The dynamic structural scaffold and diverse functional roles of GSTs make them important for enzyme engineering and for exploring novel biotechnological applications. The present study reported a significant gain-of-function activity in GST caused by a point mutation at the conserved F136 residue. The fluorescence quenching and kinetic data suggested that both binding affinity and catalytic efficiency of the mutant enzyme to the substrates 1-chloro-2,4-dinitrobenzene (CDNB), as well as the glutathione (GSH), is increased. Molecular docking showed that the mutation improves the binding interactions of the GSH with several binding-site residues. The simulation of molecular dynamics revealed that the mutant enzyme gained increased structural rigidity than the wild-type enzyme. The mutation also altered the residue interaction network (RIN) of the GSH-binding residues. These phenomena suggested that mutations led to conformational alterations and dominant differential motions in the enzyme that lead to increased rigidity and modifications in RIN. Collectively, engineering GST with a single point mutation at conserved F136 can significantly increase its xenobiotic activity by increasing the catalytic efficiency that may be exploited for biotechnological applications. • GSTs are ideal enzymes for engineering as they present important biotechnological applications. • A point mutation at the conserved F136 residue causes significant gain-of-function activity in GST. • The binding affinity, as well as catalytic efficiency of the mutant enzyme, was increased. • Mutation improves the binding interactions of the GSH with enzyme binding-site. • Engineering GST with conserved F136 mutation considerably increased its xenobiotic degrading activity. [ABSTRACT FROM AUTHOR]

Fascioliasis, caused by the liver fluke Fasciola gigantica, is a significant zoonotic disease of the livestock and human, causing substantial economic loss worldwide. Triclabendazole (TCBZ) is the only drug available for the management of the disease against which there is an alarming increase in drug resistance. No vaccine is available commercially for the protection against this disease. Increasing resistance to TCBZ and the lack of a successful vaccine against fascioliasis demands the development of vaccines. In the present study, a structural immunoinformatics approach was used to design a multi-epitope subunit vaccine using the glutathione S-transferase (GST) protein of Fasciola gigantica. The GST antigen is a safe, non-allergic, highly antigenic, and effective vaccine candidate against various parasitic flukes and worms. The cytotoxic T lymphocytes, helper T lymphocytes, and B-cell epitopes were selected for constructing the vaccine based on their immunogenic behavior and binding affinity. The physicochemical properties, allergenicity, and antigenicity of the designed vaccine were analyzed. To elucidate the tertiary structure of the vaccine, homology modeling was performed, followed by structure refinement and docking against the TLR2 immune receptor. Molecular dynamics simulations showed a stable interaction between the vaccine and the receptor complex. Finally, in silico cloning was performed to evaluate the expression and translation of the vaccine construct in the E. coli expression system. Further studies require experimental validation for the safety and immunogenic behavior of the designed vaccine. • Fascioliasis is a neglected tropical disease affecting both livestock and human. • A multi-epitope subunit vaccine was designed using the GST protein of F. gigantica. • CTL, HTL, and B-cell epitopes were selected for designing the vaccine based on immunogenic nature and binding affinity. • The designed vaccine showed potent immunogenicity by exhibiting INF-γ and humoral response. • Computational studies unveiled key interactions between the designed vaccine and the immune receptor. • In silico cloning confirm the expression of the engineered vaccine in a bacterial system. [ABSTRACT FROM AUTHOR]

Fascioliasis, a serious helminth disease of the livestock population, results from infection with the parasite Fasciola. Despite the alarming increase in drug resistance, a safe and fully effective vaccine for fascioliasis is still not available. In the present study, we employed high-throughput immunoinformatics approaches to design a multi-epitope based subunit vaccine using seven important F. gigantica proteins (cathepsin B, cathepsin L, leucyl aminopeptidase, thioredoxin glutathione reductase, fatty acid binding protein-1, saposin-like protein-2, and 14–3-3 protein epsilon). The CTL, HTL, and B-cell epitopes were selected for designing the vaccine on the basis of their immunogenic behavior and binding affinity. The engineered vaccine showed potential immunogenic efficacy by elaborating the IFN-γ and humoral response. The modeled structure of the vaccine was docked with the toll-like receptor-2 immune receptor, and the molecular dynamics simulation was performed to understand the stability, interaction, and dynamics of the complex. Finally, in silico cloning of the resulting vaccine was performed to create the plasmid construct of vaccine for expression in an appropriate biological system. Experimental evaluation of the designed vaccine construct in an animal model may result in a novel and immunogenic vaccine that may confer protection against F. gigantica infection. • Fascioliasis is a foodborne neglected diseases effecting both livestock and cattles. • A multi-epitope subunit vaccine was designed by exploring seven antigenic proteins from F. gigantica. • Engineered vaccine showed potential immunogenicity efficacy. • Key interactions between designed vaccine and immune receptor were identified. • In silico cloning confirm vaccine expression in bacterial expression system. [ABSTRACT FROM AUTHOR]

Thioredoxin glutathione reductase (TGR), a potential anthelminthic drug target causes NADPH-dependent transfer of electrons to both thioredoxins and glutathione systems. In the present study, we showed that a single point mutation conserved at Arg451 position is critical for maintaining the structure-function of FgTGR. The current biochemical results showed that R451A mutation significantly decreases both oxidoreductase activities (glutathione reductase and thioredoxin reductase) of the enzyme. Computational analyses using molecular dynamics simulation provided an in-depth insight into the structural alterations caused as a result of the mutation. Furthermore, the different regions of the mutant FgTGR structure were found to be altered in flexibility/rigidity as a result of the mutation. This led to mutant-specific conformational alterations and dominant differential motions that contributed to the abrogated function of mutant FgTGR. These results were confirmed using GdnHCl-induced denaturation-based stability studies. Moreover, mutation reduced the free energy of stabilization of the protein, thereby destabilizing the mutant protein structure. Therefore, these findings displayed differential dynamics in the FgTGR structure and highlighted the relevance of residue-level interactions in the protein. Thus, the current study provided a basis for exploiting regions other than the active site of TGR for inhibitory effect and development of novel antihelminthics. • R451A mutation significantly decreases GR and TrxR activities of the enzyme. • Different regions of the mutant FgTGR structure were altered in flexibility/rigidity. • Conformational alterations and dominant differential motions cause abrogated function of mutant FgTGR. • Mutation also destabilized the protein structure by lowering its free energy of stabilization. • Results show differential dynamics in the FgTGR structure and reveal importance of residue-level interactions in the protein. [ABSTRACT FROM AUTHOR]