Computational exploration of natural compounds targeting Staphylococcus aureus: inhibiting AgrA promoter binding for antimicrobial intervention.

Staphylococcus aureus is a highly virulent nosocomial pathogen that poses a significant threat to individuals exposed to healthcare settings. Due to its sophisticated machinery for producing virulence factors, S. aureus can cause severe and potentially fatal infections in humans. This study focuses on the response regulator AgrA, which plays a crucial role in regulating the production of virulence factors in S. aureus. The objective is to identify natural compounds that can inhibit the binding of AgrA to its promoter site, thus inhibiting the expression of virulence genes. To achieve this, a pharmacophore model was generated using known drugs and applied to screen the ZINC natural product database. The resulting compounds were subjected to molecular docking-based virtual screening against the C-terminal DNA binding domain of AgrA. Three compounds, namely ZINC000077269178, ZINC000051012304, and ZINC000004266026, were shortlisted based on their strong affinity for key residues involved in DNA binding and transcription initiation. Subsequently, the unbound and ligand-bound complexes were subjected to a 200 ns molecular dynamics simulation to assess their conformational stability. Various analyses, including RMSD, RMSF, Rg, SASA, Principal Component Analysis, and Gibbs free energy landscape, were conducted on the simulation trajectory. The RMSD profile indicated similar fluctuations in both bound and unbound structures, while the Rg profile demonstrated the compactness of the protein without any unfolding during the simulation. Furthermore, Principal component analysis revealed that ligand binding reduced the overall atomic motion of the protein whereas free energy landscape suggested the energy variations obtained in complexes.Communicated by Ramaswamy H. Sarma.

In-silico design of an immunoinformatics based multi-epitope vaccine against Leishmania donovani.

BACKGROUND: Visceral Leishmaniasis (VL) is a fatal vector-borne parasitic disorder occurring mainly in tropical and subtropical regions. VL falls under the category of neglected tropical diseases with growing drug resistance and lacking a licensed vaccine. Conventional vaccine synthesis techniques are often very laborious and challenging. With the advancement of bioinformatics and its application in immunology, it is now more convenient to design multi-epitope vaccines comprising predicted immuno-dominant epitopes of multiple antigenic proteins. We have chosen four antigenic proteins of Leishmania donovani and identified their T-cell and B-cell epitopes, utilizing those for in-silico chimeric vaccine designing. The various physicochemical characteristics of the vaccine have been explored and the tertiary structure of the chimeric construct is predicted to perform docking studies and molecular dynamics simulations. RESULTS: The vaccine construct is generated by joining the epitopes with specific linkers. The predicted tertiary structure of the vaccine has been found to be valid and docking studies reveal the construct shows a high affinity towards the TLR-4 receptor. Population coverage analysis shows the vaccine can be effective on the majority of the world population. In-silico immune simulation studies confirms the vaccine to raise a pro-inflammatory response with the proliferation of activated T and B cells. In-silico codon optimization and cloning of the vaccine nucleic acid sequence have also been achieved in the pET28a vector. CONCLUSION: The above bioinformatics data support that the construct may act as a potential vaccine. Further wet lab synthesis of the vaccine and in vivo works has to be undertaken in animal model to confirm vaccine potency.

Threshold phosphorus level of acidic soils of eastern India.

It is imperative to have a practical indicator for assessing the potential for phosphorus movement from soil to surface waters causing environmental pollution. The present study was undertaken with two groups of acidic soils from the terai and red and laterite agro-climatic zone of eastern India to estimate their phosphorus threshold values and establish a simple model with the clay content as the principal variable. The mean phosphorus adsorption maximum and phosphorus buffering capacity were higher in lateritic than terai soil. The change-point soil test values at which water soluble phosphorus enhanced abruptly ranged from 32 to 68 mg kg-1 and 28 to 63 mg kg-1 with Bray-1 and Mehlich-1 method, respectively, for the soils of the terai zone. Similarly, it varied from 47 to 90 mg kg-1 and 44 to 89 mg kg-1, respectively, for the lateritic soils. Application of phosphatic fertilizers should not be allowed beyond the threshold level, which was considered 75% of the change-point soil test value to avoid the risk of the soil becoming a source of phosphorus pollution for surface water bodies. The simplified models of phosphorus threshold level (mg kg-1) developed with either of the extractants were "4.75 × clay content (%) - 30" and "6.00 × clay content (%) - 75" for terai and lateritic soil, respectively. These models can be extended to the soils with similar mineralogy but varying in clay content for sustainable phosphorus management without limiting crop production.