Computational evaluation of phytochemicals targeting DNA topoisomerase I in Leishmania donovani: molecular docking and molecular dynamics simulation studies.

DNA topoisomerase I (Topo I) is a ubiquitous enzyme that plays a crucial role in resolving the topological constraints of supercoiled DNA during various cellular activities, including repair, replication, recombination, transcription, and chromatin remodeling. Multiple studies have confirmed the essential role of Topo I in nucleic acid metabolism of Leishmania donovani, the kinetoplastid parasite responsible for visceral leishmaniasis or kala-azar. Inhibition of this enzyme has shown promise as a strategy for therapy against visceral leishmaniasis. However, current treatment options suffer from limitations related to effectiveness, cost, and side effects. To address these challenges, computational methods have been employed in this study to investigate the inhibition of Leishmania donovani DNA topoisomerase I (LdTopo I) by phytochemicals derived from Indian medicinal plants known for their anti-leishmanial activity. A library of phytochemicals and known inhibitors was assembled, and virtual screening based on docking binding affinities was conducted to identify potent phytochemical inhibitors. To assess the drug-likeness of the docked phytochemicals, their physicochemical properties were predicted. Additionally, molecular dynamics (MD) simulations were performed on the docked complexes for a duration of 100 ns to evaluate their stability, intermolecular interactions, and dynamic behavior. Among all the docked phytochemicals, three compounds, namely CID23266147 (withanolide N), CID5488537 (fagopyrine), and CID100947536 (isozeylanone), exhibited the highest inhibitory potential against LdTopo I. These findings hold promise for the development of novel inhibitors targeting LdTopo I, which could potentially lead to improved therapies for visceral leishmaniasis.Communicated by Ramaswamy H. Sarma.

Identification of phytochemical inhibitors targeting phosphate acetyltransferase of Mycoplasma genitalium: insights from virtual screening and molecular dynamics studies.

Mycoplasma genitalium (M. genitalium) has evolved as a superbug, and the developing antimicrobial resistance with just a few treatment options available is an imminent concern. Due to the emergence of antibiotic resistance, a new antibiotic class or medications are required to combat this pathogen. The phosphate acetyltransferase (PTA) enzyme can be a suitable drug target which is essential for M. genitalium survival and involves in acetate metabolism. To efficiently find potent inhibitors, structure-based drug design approaches targeting the PTA of M. genitalium have been established. In this study, the three most potent phytochemical inhibitors were predicted from virtual screening and these are sitostanyl ferulate, beta-sitosterol-beta-D-glucoside, and brassinolide, with binding energies of - 9.66, - 9.60, and - 9.48 kcal/mol, respectively. The active site residues Thr-125, Arg-300, Ser-299, Tyr-272, and Lys-273 appear to be critical in binding the three predicted potent inhibitors. The results of the molecular dynamics study indicate that the three predicted phytochemical inhibitors have formed stable bonds with PTA. Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) was utilized for the estimation of binding free energy of PTA-phytochemical complexes. Taken together, the findings of our computational work might aid in the development of possible potential drugs to treat and ameliorate the severity of M. genitalium infection.

Potential therapeutic targets for combating Mycoplasma genitalium.

Mycoplasma genitalium (M. genitalium) has emerged as a sexually transmitted infection (STI) all over the world in the last three decades. It has been identified as a cause of male urethritis, and there is now evidence that it also causes cervicitis and pelvic inflammatory disease in women. However, the precise role of M. genitalium in diseases such as pelvic inflammatory disease, and infertility is unknown, and more research is required. It is a slow-growing organism, and with the advent of the nucleic acid amplification test (NAAT), more studies are being conducted and knowledge about the pathogenicity of this organism is being elucidated. The accumulation of data has improved our understanding of the pathogen and its role in disease transmission. Despite the widespread use of single-dose azithromycin in the sexual health field, M. genitalium is known to rapidly develop antibiotic resistance. As a result, the media frequently refer to this pathogen as the "new STI superbug." Despite their rarity, antibiotics available today have serious side effects. As the cure rates for first-line antimicrobials have decreased, it is now a challenge to determine the effective antimicrobial therapy. In this review, we summarise recent M. genitalium research and investigate potential therapeutic targets for combating this pathogen.