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

Autor: Muhammad S; Central labs, King Khalid University, AlQura'a, P. O. Box 906, Abha, Saudi Arabia; Department of Chemistry, College of Science, King Khalid University, P. O. Box 9004, Abha 61413, Saudi Arabia. Electronic address: mshabbir@kku.edu.sa., Faiz A; Department of Chemistry, University of Agriculture Faisalabad, Faisalabad 38000, Pakistan., Bibi S; Department of Chemistry, University of Agriculture Faisalabad, Faisalabad 38000, Pakistan. Electronic address: shamsa.shafiq@uaf.edu.pk., Rehman SU; Department of Chemistry, University of Agriculture Faisalabad, Faisalabad 38000, Pakistan. Electronic address: shafiq.urrehman@uaf.edu.pk., Alshahrani MY; Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, P.O. Box 9088, Abha 61413, Saudi Arabia.
Jazyk: angličtina
Zdroj: Computational biology and chemistry [Comput Biol Chem] 2024 Dec; Vol. 113, pp. 108218. Date of Electronic Publication: 2024 Sep 30.
DOI: 10.1016/j.compbiolchem.2024.108218
Abstrakt: 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.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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Databáze: MEDLINE