Coronavirus pandemic has caused a vast number of deaths worldwide. Thus creating an urgent need to develop effective counteragents against novel coronavirus disease (COVID-19). Many antiviral drugs have been repurposed for treatment but implicated minimal recovery, which further advanced the need for clearer insights and innovation to derive effective therapeutics. Strategically, Noscapine, an approved antitussive drug with positive effects on lung linings may show favorable outcomes synergistically with antiviral drugs in trials. Hence, we have theoretically examined the combinatorial drug therapy by culminating the existing experimental results with in silico analyses. We employed the antitussive noscapine in conjugation with antiviral drugs (Chloroquine, Umifenovir, Hydroxychloroquine, Favlplravir and Galidesivir). We found that Noscapine-Hydroxychloroquine (Nos-Hcq) conjugate has strong binding affinity for the main protease (Mpro) of SARS-CoV-2, which performs key biological function in virus infection and progression. Nos-Hcq was analyzed through molecular dynamics simulation. The MD simulation for 100 ns affirmed the stable binding of conjugation unprecedentedly through RMSD and radius of gyration plots along with critical reaction coordinate binding free energy profile. Also, dynamical residue cross-correlation map with principal component analysis depicted the stable binding of Nos-Hcq conjugate to Mpro domains with optimal secondary structure statistics of complex dynamics. Also, we reveal the drugs with stable binding to major domains of Mpro can significantly improve the work profile of reaction coordinates, drug accession and inhibitory regulation of Mpro. The designed combinatorial therapy paves way for further prioritized in vitro and in vivo investigations for drug with robust binding against Mpro of SARS-CoV-2.
Mycobacterium tuberculosis (Mtb) resistance toward anti-tuberculosis drugs is a widespread problem. Pyrazinamide (PZA) is a first line antitubercular drug that kills semi-dormant bacilli when converted into its activated form, that is, pyrazinoic acid (POA) by Pyrazinamidase (PZase) enzyme coded by pncA gene. In this study, we conducted several analyses on native and mutant structures (W68R, W68G) of PZase before and after docking with the PZA drug to explore the molecular mechanism behind PZA resistance caused due to pncA mutations. Structural changes caused by mutations were studied with respect to their effects on functionality of protein. Docking was performed to analyze the protein-drug binding and comparative analysis was done to observe how the mutations affect drug binding affinity and binding site on protein. Native PZase protein was observed to have the maximum binding affinity in terms of docking score as well as shape complementarity in comparison to the mutant forms. Molecular dynamics simulation analyses showed that mutation in the 68th residue of protein results in a structural change at its active site which further affects the biological function of protein, that is, conversion of PZA to POA. Mutations in the protein thereby led to PZA resistance in the bacterium due to the inefficient binding.
Development of effective counteragents against the novel coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains, requires clear insights and information for understanding the immune responses associated with it. This global pandemic has pushed the healthcare system and restricted the movement of people and succumbing of the available therapeutics utterly warrants the development of a potential vaccine to contest the deadly situation. In the present study, highly efficacious, immunodominant cytotoxic T-lymphocyte (CTL) epitopes were predicted by advanced immunoinformatics assays using the spike glycoprotein of SARS-CoV2, generating a robust and specific immune response with convincing immunological parameters (Antigenicity, TAP affinity, MHC binder) engendering an efficient viral vaccine. The molecular docking studies show strong binding of the CTL construct with MHC-1 and host membrane specific TLR2 receptors. The molecular dynamics simulation in an explicit system confirmed the stable and robust binding of CTL epitope with TLR2. Steep magnitude RMSD variation and compelling residual fluctuations existed in terminal residues and various loops of the β linker segments of TLR2-epitope (residues 105-156 and 239-254) to about 0.4 nm. The reduced Rg value (3.3 nm) and stagnant SASA analysis (275 nm/S2/N after 8 ns and 5 ns) for protein surface and its orientation in the exposed and buried regions suggests more compactness due to the strong binding interaction of the epitope. The CTL vaccine candidate establishes a high capability to elicit the critical immune regulators, like T-cells and memory cells as proven by the in silico immunization assays and can be further corroborated through in vitro and in vivo assays.
Chikungunya fever presents as a high-grade fever during its Background: acute febrile phase and can be prolonged for months as chronic arthritis in affected individuals. Currently, there are no effective drugs or vaccines against this virus. The present study was undertaken to evaluate protein-ligand interactions of all chikungunya virus (CHIKV) proteins with natural compounds from a MolBase library in order to identify potential inhibitors of CHIKV.Virtual screening of the natural compound library against four Methods: non-structural and five structural proteins of CHIKV was performed. Homology models of the viral proteins with unknown structures were created and energy minimized by molecular dynamic simulations. Molecular docking was performed to identify the potential inhibitors for CHIKV. The absorption, distribution, metabolism and excretion (ADME) toxicity parameters for the potential inhibitors were predicted for further prioritization of the compounds.Our analysis predicted three compounds, Catechin-5-O-gallate, Results: Rosmarinic acid and Arjungenin, to interact with CHIKV proteins; two (Catechin-5-O-gallate and Rosmarinic acid) with capsid protein, and one (Arjungenin) with the E3.The
The enzyme Pantothenate synthetase (PS) represents a potential drug target in Mycobacterium tuberculosis. Its X-ray crystallographic structure has demonstrated the significance and importance of conserved active site residues including His44, His47, Asn69, Gln72, Lys160 and Gln164 in substrate binding and formation of pantoyl adenylate intermediate. In the current study, molecular mechanism of decreased affinity of the enzyme for ATP caused by alanine mutations was investigated using molecular dynamics (MD) simulations and free energy calculations. A total of seven systems including wildtype + ATP, H44A + ATP, H47A + ATP, N69A + ATP, Q72A + ATP, K160A + ATP and Q164A + ATP were subjected to 50 ns MD simulations. Docking score, MM-GBSA and interaction profile analysis showed weak interactions between ATP (substrate) and PS (enzyme) in H47A and H160A mutants as compared to wild-type, leading to reduced protein catalytic activity. However, principal component analysis (PCA) and free energy landscape (FEL) analysis revealed that ATP was strongly bound to the catalytic core of the wild-type, limiting its movement to form a stable complex as compared to mutants. The study will give insight about ATP binding to the PS at the atomic level and will facilitate in designing of nonreactive analogue of pantoyl adenylate which will act as a specific inhibitor for PS.The causative agent of tuberculosis (TB) is Mycobacterium tuberculosis (Mtb), a major infectious bacterium which spreads through droplets in the air. TB is second only to HIV/AIDS as the major killer across the globe 1 . Multi-drug resistant Mtb is becoming a regular health problem especially in immuno-compromised individuals with HIV 2 . This form of TB is more difficult to treat and as a result has higher mortality rate. Because of this, the discovery of drugs targeting novel pathways such as the synthesis of pantothenate has become increasingly important. The World Health statistics report in 2014 stated that 9.6 million people were diagnosed with TB of which 1.5 million people died 3 . PanC gene encodes Pantothenate Synthetase (PS; EC 6.3.2.1) responsible for producing pantothenate (vitamin B5), is a promising drug target owing to a few important reasons 4 . Firstly, it is present in all bacteria but absent in mammals, a key factor for the selective activity of drug molecule 5 . Secondly, Pantothenate is notable for its role in the synthesis of coenzyme A (CoA) and acyl carrier protein (ACP), essential components of fatty acid synthesis which maintain persistent growth and pathogenicity of the M. tuberculosis 6 . Lastly, Jacob et al., conducted research on a TB vaccine which compromised panC auxotrophs' growth and virulence rigorously supporting the theory of functional necessity of Pantothenate Synthetase pathway and enhancing its attractiveness as a potential antimicrobial target 7 . PS proceeds by Bi Uni Uni Bi Ping Pong kinetic reactions; it catalyzes the ATP dependent condensation of pantoate with beta-alanine via a pantoyl adenylate intermediate as follo...
The apoptotic mechanism is regulated by the BCL-2 family of proteins, such as BCL-2 or Bcl-xL, which block apoptosis while Bad, Bak, Bax, Bid, Bim or Hrk induce apoptosis. The overexpression of BCL-2 was found to be related to the progression of cancer and also providing resistance towards chemotherapeutic treatments. In the present study, we found that all polyphenols (apigenin, fisetin, galangin and luteolin) bind to the hydrophobic groove of BCL-2 and the interaction is stable throughout MD simulation run. Luteolin was found to bind with highest negative binding energy and thus, claimed highest potency towards BCL-2 inhibition followed by fisetin. The hydrophobic interactions were found to be critical for stable complex formation as revealed by the vdW energy and ligplot analysis. Finally, on the basis of data obtained during the study, it can be concluded that these polyphenols have the potential to be used as lead molecules for BCL-2 inhibition.
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