Jaganathan Ramakrishnan

Topoisomerase II (Topo II) is a nuclear gatekeeper of genome integrity, essential for unwinding DNA during replication and resolving chromosomal tangles during segregation. This indispensable function positions Topo II as a clinically validated target for proliferating cells, driving its exploitation as a therapeutic target for cancer and infectious diseases. However, adverse effects and emerging resistance limit the clinical utility of existing Topo II inhibitors, necessitating the identification of novel, safer candidates. In this study, a comprehensive in silico workflow was employed to identify and characterize potential Topo II inhibitors from the PubChem database. A curated library of four novel compounds (PUBCHEM IDs: 33113, 44439747, 49784442, and 49840836) was subjected to structure-based virtual screening using molecular docking, followed by 100 ns molecular dynamics (MD) simulations and comprehensive ADMET profiling. Molecular docking identified exceptional binding affinities ranging from -10.1 to -11.3 kcal/mol, with compound 49840836 exhibiting superior target engagement through optimal interactions with catalytic residues GLU 66, ASN 70, and ASP 73. Notably, LYS 367 emerged as a universal interaction partner. However, subsequent MD simulations challenged the static docking hierarchy: compound 44439747 demonstrated exceptional dynamic stability (RMSD ~0.75–0.8 nm) and persistent hydrogen bonding, correlating with favorable residence time despite moderate affinity. ADMET profiling revealed favorable cardiac and neurological safety profiles yet identified concerning uniform liabilities, including high risks of Drug-Induced Liver Injury, nephrotoxicity, and genotoxicity. Candidate prioritization identifies 49840836 for potency-driven indications and 44439747 for sustained target engagement scenarios. Overall, this integrated computational profiling approach validates a cost-effective screening paradigm combining binding energetics, conformational dynamics, and ADMET properties, establishing a robust foundation for the rational design and experimental validation of next-generation Topo II inhibitors with enhanced stability and differentiated safety profiles.

Curcumin, a plant‐polyphenolic compound, has been reported to induce autophagy and autophagic cell death in insect cells but its impact on cell cycle regulation is not well understood. In this study, we investigated the short‐term effects of curcumin on the cell proliferation, cell cycle progression and autophagy‐associated cellular responses in the Sf9 insect cells of Spodoptera frugiperda . Short‐term treatment of Sf9 cells with low‐dose curcumin (5–15 µg/mL) resulted in a continuous decrease in cell proliferation in a dose and time dependent manner. Flow cytometric analysis showed a significant increase in the number of cells in the G 1 phase, indicating G 1 cell cycle arrest. This was also supported by nuclear morphology analysis using DAPI staining. Importantly, the growth inhibition caused by curcumin was not associated with apoptotic features or DNA fragmentation. Treatment with curcumin evoked a time‐dependent increase in intracellular reactive oxygen species without significant mitochondrial membrane depolarization, indicating a controlled stress response instead of mitochondrial‐dependent apoptosis. Scanning electron microscopy revealed significant surface morphological remodeling including cell shrinkage and membrane irregularities consistent with structural reorganization associated with autophagy. Molecular docking analysis using conserved insect cell cycle regulatory proteins supported a potential interaction of curcumin with G ₁ phase cyclin‐dependent kinases. Taken together, the findings demonstrate that curcumin induces autophagy‐linked G ₁ cell cycle arrest in Sf9 cells, extending previous observations of curcumin‐induced autophagy and nucleophagy. This study highlights autophagy‐mediated cell cycle regulation as a key mechanism underlying curcumin‐induced growth suppression in insect cells and provides insight into the cellular actions of botanical bioactive compounds relevant to insect physiology.

This study investigates the binding affinity and interactions of the Furin enzyme with two inhibitors, Naphthofluorescein and decanoyl-RVKR-chloromethylketone (CMK), using molecular docking and molecular dynamics (MD) simulations. Molecular docking results showed binding affinities of − 9.18 kcal/mol for CMK and − 5.39 kcal/mol for Naphthofluorescein. To further understand the stability and conformational changes of these complexes, MD simulations were performed. Despite CMK’s favorable docking score, MD simulations revealed that its binding interactions at the Furin-active site were unstable, with significant changes observed during the simulation. In contrast, Naphthofluorescein maintained strong and stable interactions throughout the MD simulation, as confirmed by RMSD and RMSF analyses. The binding-free-energy analysis also supported the stability of Naphthofluorescein. These findings indicate that Naphthofluorescein exhibits greater stability and binding affinity as a Furin inhibitor compared to CMK. The results of this in-silico study suggest that Naphthofluorescein, along with CMK, holds the potential for repurposing as a treatment for COVID-19, subject to further validation through clinical studies.

Currently, no approved drug is available as a causative agent of coronavirus disease 2019 (COVID‐19) except for some repurposed drugs. The first structure of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) was reported in late 2019, based on that some vaccines and repurposed drugs were approved to prevent people from COVID‐19 during the pandemic situation. Since then, new types of variants emerged and notably, the receptor binding domain (RBD) adopted different binding modes with angiotensin‐converting enzyme 2 (ACE2); this made significant changes in the progression of COVID‐19. Some of the new variants are highly infectious spreading fast and dangerous. The present study is focused on understanding the binding mode of the RBD of different mutated SARS‐CoV‐2 variants of concern (alpha to omicron) with the human ACE2 using molecular dynamics simulation. Notably, some variants adopted a new binding mode of RBD with ACE2 and formed different interactions, which is unlike the wild type; this was confirmed from the comparison of interaction between RBD‐ACE2 of all variants with its wild‐type structure. Binding energy values confirm that some mutated variants exhibit high binding affinity. These findings demonstrate that the variations in the sequence of SARS‐CoV‐2 S‐protein altered the binding mode of RBD; this may be the reason that the virus has high transmissibility and causes new infections. This in‐silico study on mutated variants of SARS‐CoV‐2 RBD with ACE2 insights into their binding mode, binding affinity, and stability. This information may help to understand the RBD‐ACE2 binding domains, which allows for designing newer drugs and vaccines.

Since 2019 the SARS-CoV-2 and its variants caused COVID-19, such incidents brought the world in pandemic situation. This happened due to furious mutations in SARS-CoV-2, in which some variants had high transmissibility and infective, this led the virus emerged as virulent and worsened the COVID-19 situation. Among the variants, P323L is one of the important mutants of RdRp in SARS-CoV-2. To inhibit the erroneous function of this mutated RdRp, we have screened 943 molecules against the P323L mutated RdRp with the criteria that the molecules with 90% similar to the structure of remdesivir (control drug) resulted nine molecules. Further, these molecules were evaluated by induced fit docking (IFD) identified two molecules (M2 & M4) which are forming strong intermolecular interactions with the key residues of mutated RdRp and has high binding affinity. Docking score of the M2 and M4 molecules with mutated RdRp are -9.24 and -11.87 kcal/mol, respectively. Further, to understand the intermolecular interactions, conformational stability, the molecular dynamics simulation and binding free energy calculations were performed. The binding free energy values of M2 and M4 molecules with the P323L mutated RdRp complexes are -81.60 and -83.07 kcal/mol, respectively. The results of this in silico study confirm that M4 is a potential molecule; hence, it may be considered as the potential inhibitor of P323L mutated RdRp to treat COVID-19 after clinical investigation.Communicated by Ramaswamy H. Sarma

Lawsonia inermis (henna) has been used in traditional medicine throughout the world and biological property of its flower has been least explored. In the present study, the phytochemical characterization and biological activity (in vitro radical scavenging activity, anti-alpha glucosidase and anti-acetylcholinesterase) of aqueous extract prepared from henna flower (HFAE) was carried out by both Qualitative and quantitative phytochemical analysis and Fourier-transform infrared spectroscopy revealed the functional group of the phytoconstituents such as phenolics, flavonoids, saponin, tannins and glycosides. The phytochemicals present in HFAE was preliminary identified by liquid chromatography/electrospray ionization tandem mass spectrometry. The HFAE showed potent in vitro antioxidant activity and the HFAE inhibited mammalian α-glucosidase (IC₅₀ = 129.1 ± 5.3 µg/ml; Ki = 38.92 µg/ml) and acetylcholinesterase (AChE; IC₅₀ = 137.77 ± 3.5 µg/ml; Ki = 35.71 µg/ml) activity by competitive manner. In silico molecular docking analysis revealed the interaction of active constituents identified in HFAE with human α-glucosidase and AChE. Molecular dynamics simulation for 100 ns showed the stable binding of top two ligand/enzyme complexes with lowest binding energy such as 1,2,3,6-Tetrakis-O-galloyl-beta-D-glucose (TGBG)/human α-glucosidase, Kaempferol 3-glucoside-7-rhamnoside (KGR)/α-glucosidase, agrimonolide 6-O-β-D-glucopyranoside (AMLG)/human AChE and KGR/AChE. Through MM/GBSA analysis, the binding energy for TGBG/human α-glucosidase, KGR/α-glucosidase, AMLG/human AChE and KGR/AChE was found to be −46.3216, −28.5772, −45.0077 and −47.0956 kcal/mol, respectively. Altogether, HFAE showed an excellent antioxidant, anti-alpha glucosidase and anti-AChE activity under in vitro. This study suggest HFAE with remarkable biological activities could be further explored for therapeutics against type 2 diabetes and diabetes-associated cognitive decline. Communicated by Ramaswamy H. Sarma

In this COVID-19 pandemic situation, an appropriate drug is urgent to fight against this infectious disease to save lives and prevent mortality. Repurposed drugs and vaccines are the immediate solutions for this medical emergency until discover a new drug to treat this disease. As of now, no specific drug is available to cure this disease completely. Several drug targets were identified in SARS-CoV-2, in which RdRp protein is one of the potential targets to inhibit this virus infection. In-Silico studies plays a vital role to understand the binding nature of the drugs at the atomic level against the disease targets. The present study explores the binding mechanism of reported 53 nucleoside and non-nucleoside RdRp inhibitors and Ivermectin which are in clinical trials. These molecules were screened by molecular docking simulation; in which, the molecules are showing high binding affinity and forming interactions with the key amino acids of active site of RdRp protein are chosen for molecular dynamics simulation (MD) and binding free energy analysis. The results of molecular docking and MD simulation studies reveal that IDX184 is a stable molecule and forms strong interactions with the key amino acids and shows high binding affinity towards RdRp. Hence, IDX184 may also be considered as a potential inhibitor of RdRp after clinical study. Communicated by Ramaswamy H. Sarma

The IDX17119 is a phosphonomidate-based pan-genotypic non-nucleoside inhibitor of Hepatitis C Virus (HCV) NS5B RdRp thumb-II domain. IDX17119 exhibits significant antiviral activity against HCV genotype (GT) 1a, 2a, 3a and 4a. The molecular docking analysis was performed to understand the binding and intermolecular interactions of the IDX17119 molecule at the thumb-II domain of 1a, 2a, 3a and 4a GT NS5B RdRps. The molecular dynamics simulation has been performed to determine the stability of the ligand–protein complexes. We found GT 1a complex is relatively stable compared with other drug-receptor complexes. The binding free energy calculations and free energy decomposition analysis were carried out for all the complexes, the result revealed that the increase in the unfavourable polar contribution affects the binding of IDX17119 with GT 2a NS5B RdRp compared with all other complexes. In addition to this, the effect of mutation at M423 site (M423T/V) alters the conformation and activity of the IDX17119 molecule.