European Journal of Biomedical and Pharmaceutical Sciences

IN SILICO INVESTIGATION OF INDENOIMIDAZOLE DERIVATIVES AS PROMISING ARSENAL AGAINST METHICILLIN RESISTANT STAPHYLOCOCCUS AUREUS THROUGH STAPHYLOCOCCAL PROTEIN A INHIBITION

Lamidi Waheed Babatunde Olaniyan, Leonard Ona Ehigie*, Adeola Folasade Ehigie, Opeyemi Emmanuel Atanda, Tope Tunji Odunitan and Ayodeji Adebayo Fakuade

ABSTRACT

Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant challenge in healthcare due to its intricate nature and resistance to traditional antibiotics. This study delves into addressing this issue by investigating indenoimidazole derivatives' inhibitory effects on Staphylococcal protein A (SpA). Through rigorous methodology incorporating structure based virtual screening, four derivatives were optimized and identified as having superior efficacy compared to Linezolid. The findings showed that these derivatives had better binding affinities (-11.2 to -11.7 Kcal/mol) and good Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) free energies (ranging from -5.48 to -8.41 Kcal/mol). Among these, Compound 3 (3-(2,4-dihydroxybenzylidene) amino)-3a,8a-dihydroxy-2-thioxo-1,3,3a,8a-tetrahydroindeno[1,2-d] imidazol-8(2H)-one) has the highest binding affinity (-11.7 Kcal/mol) and the most favorable Gibbs free energy profile (-8.41 Kcal/mol). The pharmacokinetic evaluation revealed that all compounds possess acceptable absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles, aligning with the Lipinski rule of five for safety. Molecular dynamics simulations showed that Compound 3 maintains stable interactions and structural integrity over time, exhibiting minimal Root Mean Square Deviation and Fluctuation (RMSD and RMSF), consistent Solvent Accessible Surface Area (SASA), and a higher number of stable hydrogen bonds (H-bonds) compared to Linezolid. By presenting specific inhibitory values against SpA, this research contributes significantly to MRSA therapeutic strategies, suggesting indenoimidazole derivatives, particularly Compound 3, as viable candidates for further drug development analysis, offering hope in the ongoing battle against antibiotic resistance.

Keywords: Methicillin resistant staphylococcus aureus, Staphylococcal protein A, Indenoimidazole, Structure based virtual screening, Molecular dynamics.