Dynamics understanding of novel solvated drug molecules against emerging infections in immunocompromised patients.

The is a Gram-negative bacterium associated with serious infections, especially in immune compromised patients. Recent studies have shown to be involved in bloodstream infection in oncology patients. As the bacterium develops resistance to several classes of antibiotics and due to the depleting efficacy of current antibiotics, serious efforts are required to identify new drug targets and unveil novel chemical scaffolds against them. The bacterial tyrosine kinase enzyme takes part in exopolysaccharides production to form a biofilm matrix layer and thus results in the promotion of aggressive and resistant infections. Also, the enzyme has no close homologous copy in the human host, which warrants its targeting by novel anti-virulent compounds. In this work, an in-depth structure based virtual screening process of complete Asinex library, ChemBridge hit2lead database and comprehensive marine natural products database (CMNPD) was performed against tyrosine kinase domain to prioritize promising lead compounds that exhibited the most favorable binding conformation to the domain and achieved stable energy. These three molecules; BBB 25784317, BBB 26580136 and 12,728,806 were highlighted as promising molecules with binding energy scores of -12.58 kcal/mol, -11.52 kcal/mol and - 11.46 kcal/mol, respectively. The control molecule (adenosine diphosphate (ADP)) also showed a strong energy score of -10.88 kcal/mol. To validate the docking results, molecular dynamics simulations in a solvation box were carried out for 100 ns. The investigation reported the systems highly stable in terms of structure secondary structure elements and also in the perspective of intermolecular docked conformation. The mean RMSD of BBB 25784317, BBB 26580136, 12,728,806 and control was 1.30 Å,1.45 Å, 1.53 Å and 1.84 Å, respectively. The intermolecular binding energies predicted by MMPBSA for BBB 25784317, BBB 26580136, 12,728,806 and control were - 57.04 kcal/mol, -49.8 kcal/mol, -47.7 kcal/mol and - 48.63 kcal/mol, respectively. From in silico drug-likeness and pharmacokinetics, the compounds are noticed as high druglike compounds featuring all parameters to be marketed. The compounds were also unveiled as having favorable adsorption, distribution, metabolism, excretion properties, and no toxicity. Experimental antibacterial evaluation of selected compounds showed that compound 12,728,806 revealed antibacterial potency towards Gram-positive and Gram-negative strains. Compound 12,728,806 exhibited zone of inhibition of 8 mm at MIC of 0.4 mg/ml. In a nutshell, the compounds are promising theoretical leads and thus can be subjected to experimental biological activities.