Targeting Shikimate Kinase Pathway of Acinetobacter baumannii: A Structure-Based Computational Approach to Identify Antibacterial Compounds

Abstract

Acinetobacter baumannii (A. baumannii) is an opportunistic bacterium that has developed multidrug resistance (MDR) to most of today’s antibiotics, posing a significant risk to human health. Considering the fact that developing novel drugs is a time-consuming and expensive procedure, this research focuses on utilizing computational resources for repurposing antibacterial agents for A. baumannii. We targeted shikimate kinase, an essential enzyme in A. baumannii, that plays a significant role in the metabolic process. The basis for generating new therapeutic compounds is to inhibit the shikimate kinase and thereby targeting the shikimate pathway. Herein, 1941 drug-like compounds were investigated in different in silico techniques for assessing drug-likeness properties, ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling, binding affinity, and conformation analysis utilizing Autodock-vina and SwissDock. CHEMBL1237, CHEMBL1237119, CHEMBL2018096, and CHEMBL39167178 were determined as potential drug candidates for suppressing shikimate kinase protein. Molecular Dynamics Simulation (MDS) results for root mean square deviation, root mean square fluctuation, hydrogen bond, and gyration radius confirm the drug candidates’ molecular stability with the target protein. According to this study, CHEMBL1237 (Lisinopril) could be the most suitable candidate for A. baumannii. Our investigation suggests that the inhibitors of shikimate kinase could represent promising treatment options for A. baumannii. However, further in vitro and in vivo studies are necessary to validate the therapeutic potential of the suggested drug candidates.

Developing phytocompound-based new drugs against multi-drug-resistant Staphylococcus aureus

“…Five models (model 1, model 2, model 3, model 4 and model 5) of the protein Staphopain B were derived from the Modeller tool and the models were validated based on their structure, several angles like torsion angles, steric clashes between atoms, etc. by discrete optimized protein energy (DOPE) value, molprobity score, Ramachandran favoured and errat score [ 49 , 55 , 56 ]. From the five models, model 3 was selected for further evaluation ( table 1 ) considering its promising features ( figure 3 ), and the RMSD of the protein was 2.376 Å in MD simulation ( figure 4 ).…”

“…To learn more about the binding stability of Staphopain B_Nimbolide, Staphopain B_Epoxyazadiradione and Staphopain B_Doxycycline complexes, MD simulation was performed in Desmond on the Linux operating system [ 48 ]. The structures of the protein–ligand complexes were hydrated using the system development tool on the cubic 3-point transferable interaction potential [ 49 ]. The generated model was then normalized to the physiological salt concentration of 0.15 M by adding Na + and Cl − charged ions [ 44 ].…”

“…For the next 24 h, the plate was kept at 37°C in the incubator and checked gently after 6, 12 and 24 h, and the zone of inhibition caused by the plant extracts was measured. [49,55,56]. From the five models, model 3 was selected for further evaluation (table 1) considering its promising features (figure 3), and the RMSD of the protein was 2.376 Å in MD simulation (figure 4).…”

Phytochemical screening, antiproliferative evaluation, and molecular docking studies of Acacia nilotica fruit from Nigeria

“…The biochemicals downloaded from PubChem (https://pubchem.ncbi.nlm.nih.gov/) as shown in Table 1 were optimized (using Density Functional Theory (DFT-B3LYP/6-31G(d,p)) method and docked with the receptors using AutoDock Vina integrated in PyRx software (Horaira et al, 2023;Krishnan et al, 2022;Kirubhanand et al, 2023;Shil et al, 2023).…”