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Pyrazinamide (PZA) is the first-line drug commonly used in treating Mycobacterium tuberculosis (Mtb) infections and reduces treatment time by 33%. This prodrug is activated and converted to an active form, Pyrazinoic acid (POA), by Pyrazinamidase (PZase) enzyme. Mtb resistance to PZA is the outcome of mutations frequently reported in pncA, rpsA, and panD genes. Among the mentioned genes, pncA mutations contribute to 72–99% of the total resistance to PZA. Thus, considering the vital importance of this gene in PZA resistance, its frequent mutations (D49N, Y64S, W68G, and F94A) were investigated through in-depth computational techniques to put conclusions that might be useful for new scaffolds design or structure optimization to improve the efficacy of the available drugs. Mutants and wild type PZase were used in extensive and long-run molecular dynamics simulations in triplicate to disclose the resistance mechanism induced by the above-mentioned point mutations. Our analysis suggests that these mutations alter the internal dynamics of PZase and hinder the correct orientation of PZA to the enzyme. Consequently, the PZA has a low binding energy score with the mutants compared with the wild type PZase. These mutations were also reported to affect the binding of Fe2+ ion and its coordinated residues. Conformational dynamics also revealed that β-strand two is flipped, which is significant in Fe2+ binding. MM-GBSA analysis confirmed that these mutations significantly decreased the binding of PZA. In conclusion, these mutations cause conformation alterations and deformities that lead to PZA resistance.

Graphic abstract The prolific spread of COVID-19 caused by a novel coronavirus (SARS-CoV-2) from its epicenter in Wuhan, China, to every nook and cranny of the world after December 2019, jeopardize the prevailing health system in the world and has raised serious concerns about human safety. Multi-directional efforts are made to design small molecule inhibitors, and vaccines and many other therapeutic options are practiced, but their final therapeutic potential is still to be tested. Using the old drug or vaccine or peptides could aid this process to avoid such long experimental procedures. Hence, here, we have repurposed a small peptide (ATLQAIAS) from the previous study, which reported the inhibitory effects of this peptide. We used in silico mutagenesis approach to design more peptides from the native wild peptide, which revealed that substitutions (T2W, T2Y, L3R, and A5W) could increase the binding affinity of the peptide towards the 3CLpro. Furthermore, using MD simulation and free energy calculation confirmed its dynamics stability and stronger binding affinities. Per-residue energy decomposition analysis revealed that the specified substitution significantly increased the binding affinity at the residue level. Our wide-ranging analyses of binding affinities disclosed that our designed peptide owns the potential to hinder the SARS-CoV-2 and will reduce the progression of SARS-CoV-2-borne pneumonia. Our research strongly suggests the experimental and clinical validation of these peptides to curtail the recent corona outbreak.

The burgeoning human population exhibited a rapid amplification in demand for timber and fuelwood and as a result, the natural population of the native tree Tecomella undulata reduced rapidly due to its high economic and medicinal significance. The recognition of appropriate regions for threatened plants in the climate change scenario is a fundamental step for the restoration and conservation of biodiversity. The current study predicts the potentially suitable areas in Pakistan for T. undulata restoration. This research identifies the highly appropriate regions for vulnerable T. undulata through the maximum entropy model from MaxEnt software. The model’s Area Under Curve 0.968 suggested its accuracy. The mean temperature of the wettest quarter, precipitation of the warmest quarter, and mean temperature in the driest quarter significantly shaped the T. undulata distribution. Future suitable areas for T. undulata were made by using RCP (4.5 and 8.5) for the years 2050 and 2070 through 19 bioclimatic variables and 66 occurrence points. The current highly suitable area for T. undulata is approximately 135,749 km2 (15.4%) while the unsuitable area identified is approximately 404,917 km2 (45.91%). The highly suitable area for T. undulata increases by 3.6–7% under climate change regimes (RCP 4.5 and RCP 8.5). The Central Punjab (District Faisalabad, Nankana sahib, Jhang, Kasur, and Okara), Salt Range, Western Khayber Pakhtunkhwa (KPK), FATA area, Eastern Balochistan, and Thar and Tharparker in Sindh are the current appropriate habitats for T. undulata. Under all future climatic circumstances, the extremely appropriate area for T. undulata was anticipated to expand, whereas the unsuitable zones would all shrink. The research would be significant for the further development of T. undulata management and conservation techniques.