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Staphylococcus aureus , a notorious member of the ESKAPE pathogens, poses significant public health challenges due to its virulence and multidrug-resistant nature, particularly in methicillin-resistant S. aureus (MRSA) strains. With the increasing threat of antibiotic resistance, there is an urgent need to develop novel antibiotic agents. This study therefore aims to explore the antibacterial potential of 1 , 2 -dibenzoylhydrazine (DBH) as a scaffold against S. aureus drug target enzymes, using integrated computational approaches. The study utilized molecular docking, lead optimization, and structure-based virtual screening techniques to evaluate the binding affinities of DBH and its derivatives against various S. aureus enzymes. Prime/MM-GBSA calculations were performed to validate the binding affinities obtained, and molecular dynamics (MD) simulations were conducted to assess the stability of the DBHs-enzyme complexes. Results indicated that, out of twenty enzymes from S. aureus examined against DBH, carotenoid dehydrosqualene synthase was predicted as a suitable target enzyme for DBH, showing a binding affinity of -8.027 kcal/mol. A lead optimization operation of the compound generated 27 DBH derivatives out of which four exhibited enhanced binding affinities compared to both DBH and a standard antibiotic, ofloxacin. The QSAR model predicted that, DBH and molecule_D_1 have higher PIC 50 of 4.779 µM compared with the standard drug (ofloxacin = 4.678 µM). MD simulations confirmed the stability of the top-scoring derivatives within the enzyme's binding pocket, with RMSD and RMSF analyses supporting their potential as inhibitors of the enzyme. In conclusion, this study has predicted the effect of DBH derivatives on S. aureus based on their in silico inhibitory capacity against the carotenoid dehydrosqualene synthase from the organism. Future work will seek to experimentally validate these findings against the suggested enzyme., Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00278-1., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Purpose: Major human parasitic protozoans, such as Plasmodium falciparum and Trypanosoma brucei, cause malaria and trypanosomiasis also known as sleeping sickness. In anti-parasitic drug discovery research, trypanothione reductase (TryR) and P. falciparum dihydroorotate dehydrogenase (Pf-DHODH) enzymes are key drug targets in T. brucei and P. falciparum, respectively. The possibility of co-infection of single host by T. brucei and P. falciparum is because both parasites exist in sub-Saharan Africa and the problem of parasite drug resistance necessitates the discovery of new scaffolds, which are strange to the organisms causing these infectious diseases-new scaffolds may help overcome established resistance mechanisms of the organisms., Method: In this study, N,N'-bis[2-(5-bromo-7-azabenzimidazol-1-yl)-2-oxoethyl]ethylene-1,3-diamine and its cyclohexyl-1,2-diamine analogue were explored for their inhibitory potential against TryR and Pf-DHODH by engaging density functional study, molecular dynamic simulations, drug-likeness, in silico and in vitro studies RESULTS/CONCLUSION: Results obtained indicated excellent binding potential of the ligands to the receptors and good ADMET (adsorption, desorption, metabolism, excretion, and toxicity) properties., (© 2023. The Author(s) under exclusive licence to Witold Stefański Institute of Parasitology, Polish Academy of Sciences.)