Yasara Dynamics Download
Rosalia Kemme
Yet Another Scientific Artificial Reality Application (YASARA) is a computer program for molecular visualising, modelling, and dynamics. It has many scientific uses, as expressed by the large number of scientific articles mentioning the software.[1] The free version of YASARA[2] is well suited to bioinformatics education. A series of freely available bioinformatics courses exist that use this software.
The pandemic unleashed by the emergence of a new strain of the SARS-CoV-2 coronavirus in late 2019, has created significant pressure on health teams and research centers to find effective treatments that can lessen the effects of this disease on the most severe patients. Different strategies have been used in medicinal chemistry, including the repositioning of approved drugs with different indications in the clinic, the reevaluation of experimental molecules, and in silico studies. In this work, we present the design and evaluation by molecular coupling and simulation by molecular dynamics of potential ligands towards four critical enzymes in the virus replication cycle based on structural characteristics of compounds with demonstrated activity against SARS-CoV and MERS, coronavirus species with some similarity to SARS-CoV-2. The results suggest that hydroxylated ligands capable of adopting a V conformation could have a good affinity for Mpro and PLpro proteases and possess antioxidant and anti-inflammatory capacity so that they could be the basis of projects for the development of new antivirals.
Several conclusions emerged from these studies. First, if some structures could be found, additional optimization of the computational hit would be needed. Secondly, molecular docking is a useful computational tool, but it should be complemented with additional studies like molecular dynamics simulations to provide additional support to the findings of structure-based virtual screening (SBVS). One of the most important conclusions is that there are molecules already used in the clinic or from natural products that could have therapeutic use against COVID-19, then it is not like all efforts must start from scratch.
In our group, we have carried out several studies on compounds in which their structures resemble those of compounds 1-4. Therefore, inspired by these structures, we decided to explore if some derivatives of anthranilic acid 6, quinazolines 7, and phenylpropanoids 8, could have a theoretical affinity for any of the four targets of SARS CoV and SARS CoV-2. For the choice of substituents, it was decided for this initial exploration that all the molecules conserve the catechol part of the helicase inhibitor 1 and the cinnamic acid portion of cinnanserin 2. Compounds bearing this molecular template have been studied for their potent anti-inflammatory and antioxidant activities (Lopes-Lutz et al., 2008; Ruan et al., 2017). This attribute could give the studied compounds additional desirable properties, as it has been reported that dysfunctional immune responses lead to the progression of the most severe cases. Thus, immunomodulatory compounds could complete the therapeutic approaches (Tay et al., 2020). In this paper, we present the in silico evaluation through molecular docking of the compounds 5-8 (Figure 1). A molecular dynamics study was carried out for the most promising compounds to obtain more information that contributes to the development of new antivirals.
In conclusion, the analysis of the molecular docking and molecular dynamics calculations carried out on this small database shows that hydroxylated compounds with certain conformational flexibility that allows them to adopt a V-shaped conformation could be starting points for new antiviral development projects. The analysis of the interaction pattern suggests that the hydroxyl groups present in these molecules are needed for their interaction with some critical residues through hydrogen bonding. MM-PBSA ligand binding energy (LBE) calculations suggest that compound 7 could have good affinity against viral proteases and compound 8 against helicase. In addition to their potential antiviral activity, they have a favorable in silico ADME/Tox profile and could have significant anti-inflammatory and immunoregulatory activities based on their structural features. Thus, they could prevent virus proliferation and modulate some of the uncontrolled immune response, which has been recently recognized as a factor related to the most severe cases (Tang et al., 2020; Tay et al., 2020). An essential point of the efforts that have arisen from the crisis generated by COVID-19 is that they should not be interrupted. Much of the research-oriented towards the development of the cure, was born in basic science or is the continuation of projects that began with the study of other viruses. A Damocles sword is tingling above us: this is the third time that we have had an epidemic (now a pandemic) event due to coronaviruses in the 21st century (SARS, MERS, COVID), so efforts to find drugs that allow the treatment of the patients most affected by this or future coronaviruses is imperative.
FIGURE 3. The molecular dynamics simulation of the peptides and RBD complex, here (A) root mean square deviation (RMSD) of the alpha carbon atom, (B) solvent accessible surface area (SASA), (C) radius of gyration (Rg), (D) hydrogen bonding of the complexes to estimate their stability in the simulation time.
Methods: YASARA Structure tool was used for homology modelling of the C-terminal CUB domains. Domain interactions between the spacer domain and CUB domains were studied by HADDOCK protein-protein docking. WT- ADAMTS13 was subjected to molecular dynamics simulations and binding free energy calculation with AMBER16. Selected residues were further mutated and the impact of these mutations on the conformation was investigated in an ELISA.
Results: Molecular docking analysis revealed the selectivity of Rosmarinic acid (RA) towards BGN and FAK. Molecular dynamics trajectory of BGN-RA-FAK and FAK-RA-BGN complexes showed the stability of structure in terms of Time vs Energy and Time vs RMSD values and revealed that binding of RA to BGN will block the interaction of FAK.
These included the niacin receptor 1 of Rattus Norvegicus (a.k.a. rGPR109A) and the banana receptor of Mus Musculus (a.k.a. mOlfr154). By replacing the first alpha-helix, N- and C-terminals by the ones of the I7 receptor of Rattus Norvegicus, the receptor is known to be integrated in the cell membrane [3]. These two Snifferomyces receptors, niacin receptor (NR1) and banana receptor (BR4), together with their I7 flanks, were to be modeled in molecular dynamics software, named YASARA. This way, a prediction method of the receptor activity could be implemented for use on both these receptors. However, the NR1-receptor is not specifically evolved to detect one of the TB-molecules, methyl nicotinate (Figure 1a), but niacin. In theory, the BR4-receptor can be reengineered in such a way that it could let the second TB-molecule, methyl phenylacetate (Figure 1b) act as an agonist.
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