Investigation of dual inhibition of antibacterial and antiarthritic drug candidates using combined approach including molecular dynamics, docking and quantum chemical methods

• Published in: Computational biology and chemistry Vol. 113; p. 108218
• Main Authors: Muhammad, Shabbir, Faiz, Amina, Bibi, Shamsa, Rehman, Shafiq Ur, Alshahrani, Mohammad Y.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-12-2024
• Subjects: Antibiotic; Gout arthritis; Molecular docking; Molecular dynamics; Quantum chemical methods; Gout arthritis; Molecular dynamics; Antibiotic; Quantum chemical methods; Molecular docking
• ISSN: 1476-9271; 1476-928X; 1476-928X
• DOI: 10.1016/j.compbiolchem.2024.108218

Emerging antibiotic resistance in bacteria threatens immune efficacy and increases susceptibility to bone degradation and arthritic disorders. In our current study, we utilized a three-layer in-silico screening approach, employing quantum chemical methods, molecular docking, and molecular dynamic methods to explore the novel drug candidates similar in structure to floroquinolone (ciprofloxacin). We investigated the interaction of novel similar compounds of ciprofloxacin with both a bacterial protein S. aureus TyrRS (1JIJ) and a protein associated with gout arthritis Neutrophil collagenase (3DPE). UTIs and gout are interconnected through the elevation of uric acid levels. We aimed to identify compounds with dual functionality: antibacterial activity against UTIs and antirheumatic properties. Our screening based on several methods, sorted out six promising ligands. Four of these (L1, L2, L3, and L6) demonstrated favorable hydrogen bonding with both proteins and were selected for further analysis. These ligands showed binding affinities of −8.3 to −9.1 kcal/mol with both proteins, indicating strong interaction potential. Notably, L6 exhibited highest binding energies of −9.10 and −9.01 kcal/mol with S. aureus TyrRS and Neutrophil collagenase respectively. Additionally, the pkCSM online database conducted ADMET analysis on all lead ligand suggested that L6 might exhibit the highest intestinal absorption and justified total clearance rate. Moreover, L6 showed a best predicted inhibition constant with both proteins. The average RMSF values for all complex systems, namely L1, L2, L3 and L6 are 0.43 Å, 0.57 Å, 0.55 Å, and 0.51 Å, respectively where the ligand residues show maximum stability. The smaller energy gap of 3.85 eV between the HOMO and LUMO of the optimized molecule L1 and L6 suggests that these are biologically active compound. All the selected four drugs show considerable stabilization energy ranging from 44.78 to 103.87 kcal/mol, which means all four compounds are chemically and physically stable. Overall, this research opens exciting avenues for the development of new therapeutic agents with dual functionalities for antibacterial and antiarthritic drug designing.
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•A three layer in silico approach was applied to study drug candidates as antibiotic and antiarthric.•Virtual screening of 100 compounds similar to ciprofloxacin was carried out.•ADMET analysis were also done to check out pharmacokinetic properties.•L6 showed best binding score and predicted IC50 with TyrRS and Neutrophil Collagenase.•Molecular dynamics simulations were conducted for the top four selected compounds.