Fragment Optimized Chalcone Derivatives Targeting OmpA Protein As a Therapeutic Approach Against Multidrug Resistant Acinetobacter Baumannii

Overview

Journal Sci Rep

Date 2025 Jan 31

PMID 39890884

Authors

Muhammad Naveed

Amina Abid

Tariq Aziz

Ayesha Saleem

Arooj Arshad

Khushbakht Javed

Hafiz Muzzammel Rehman

Ghulam Nabi

Mitub Al-Harbi

Abdullah F Alasmari

Affiliations

Soon will be listed here.

Abstract

Acinetobacter baumannii is a notorious pathogen associated with life-threatening infections, with its outer membrane protein A (OmpA) being a key contributor to its pathogenicity by targeting epithelial cell apoptosis. The study presents an in silico analysis of chalcone derivatives as potential therapeutic agents against the outer membrane protein A (OmpA) of Acinetobacter baumannii. We performed molecular docking to evaluate the binding interactions, revealing that isobavachalcone exhibited the highest binding affinity. Further fragment optimization (FOI) of isobavachalcone improved its binding energy. Additionally, ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis was conducted to assess the pharmacokinetic properties of the compounds. Antigenicity and allergenicity of the protein show that this protein is virulent and antigenic. Moreover, molecular docking was performed and the result shows that isobavachalcone showed the highest binding energy at -6.7 kcal/mol. Furthermore, for a more potent compound, fragment optimization was performed and led to a new lead compound fragment optimized isobavachalcone (FOI) which shows increased binding energy -6 kcal/mol. ADMET and toxicity analysis was performed of both the compounds isobavachalcone and FOI which revealed favorable pharmacokinetic profiles for both compounds, but toxicity analysis showed discrepancies, with the isobavachalcone exhibiting toxicity but FOI compound showing no detectable toxicity. This underscores the importance of structure optimization in drug development. Overall, chalcone derivatives show promise as antibacterial agents against A. baumannii, with computational analyses aiding in compound selection and optimization. While both isobavachalcone and its FOI showed favorable pharmacokinetics, in vivo and in vitro validation is needed to confirm their therapeutic potential.

References

Ballarotto M, Willems S, Stiller T, Nawa F, Marschner J, Grisoni F . Design of Nurr1 Agonists Fragment-Augmented Generative Deep Learning in Low-Data Regime. J Med Chem. 2023; 66(12):8170-8177. PMC: 10291550. DOI: 10.1021/acs.jmedchem.3c00485. View

Lu R, Hwang Y, Liu I, Lee C, Tsai H, Li H . Development of therapeutic antibodies for the treatment of diseases. J Biomed Sci. 2020; 27(1):1. PMC: 6939334. DOI: 10.1186/s12929-019-0592-z. View

Eberhardt J, Santos-Martins D, Tillack A, Forli S . AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python Bindings. J Chem Inf Model. 2021; 61(8):3891-3898. PMC: 10683950. DOI: 10.1021/acs.jcim.1c00203. View

Kim S, Chen J, Cheng T, Gindulyte A, He J, He S . PubChem 2023 update. Nucleic Acids Res. 2022; 51(D1):D1373-D1380. PMC: 9825602. DOI: 10.1093/nar/gkac956. View

Vieira I, Botelho E, de Souza Gomes T, Kist R, Caceres R, Zanchi F . Visual dynamics: a WEB application for molecular dynamics simulation using GROMACS. BMC Bioinformatics. 2023; 24(1):107. PMC: 10031864. DOI: 10.1186/s12859-023-05234-y. View

Oselusi S, Dube P, Odugbemi A, Akinyede K, Ilori T, Egieyeh E . The role and potential of computer-aided drug discovery strategies in the discovery of novel antimicrobials. Comput Biol Med. 2024; 169:107927. DOI: 10.1016/j.compbiomed.2024.107927. View

Jandial D, Blair C, Zhang S, Krill L, Zhang Y, Zi X . Molecular targeted approaches to cancer therapy and prevention using chalcones. Curr Cancer Drug Targets. 2014; 14(2):181-200. PMC: 4107204. DOI: 10.2174/1568009614666140122160515. View

Xu M, Wu P, Shen F, Ji J, Rakesh K . Chalcone derivatives and their antibacterial activities: Current development. Bioorg Chem. 2019; 91:103133. DOI: 10.1016/j.bioorg.2019.103133. View

Burley S, Bhikadiya C, Bi C, Bittrich S, Chao H, Chen L . RCSB Protein Data Bank (RCSB.org): delivery of experimentally-determined PDB structures alongside one million computed structure models of proteins from artificial intelligence/machine learning. Nucleic Acids Res. 2022; 51(D1):D488-D508. PMC: 9825554. DOI: 10.1093/nar/gkac1077. View

Barati H, Fekrirad Z, Jalali Nadoushan M, Rasooli I . Anti-OmpA antibodies as potential inhibitors of Acinetobacter baumannii biofilm formation, adherence to, and proliferation in A549 human alveolar epithelial cells. Microb Pathog. 2023; 186:106473. DOI: 10.1016/j.micpath.2023.106473. View

10.

Nguyen M, Joshi S . Carbapenem resistance in Acinetobacter baumannii, and their importance in hospital-acquired infections: a scientific review. J Appl Microbiol. 2021; 131(6):2715-2738. DOI: 10.1111/jam.15130. View

11.

Elmaidomy A, Shady N, Abdeljawad K, Elzamkan M, Helmy H, Tarshan E . Antimicrobial potentials of natural products against multidrug resistance pathogens: a comprehensive review. RSC Adv. 2022; 12(45):29078-29102. PMC: 9558262. DOI: 10.1039/d2ra04884a. View

12.

Ayoub Moubareck C, Hammoudi Halat D . Insights into : A Review of Microbiological, Virulence, and Resistance Traits in a Threatening Nosocomial Pathogen. Antibiotics (Basel). 2020; 9(3). PMC: 7148516. DOI: 10.3390/antibiotics9030119. View

13.

Dallakyan S, Olson A . Small-molecule library screening by docking with PyRx. Methods Mol Biol. 2015; 1263:243-50. DOI: 10.1007/978-1-4939-2269-7_19. View

14.

Castanheira M, Mendes R, Gales A . Global Epidemiology and Mechanisms of Resistance of Acinetobacter baumannii-calcoaceticus Complex. Clin Infect Dis. 2023; 76(Suppl 2):S166-S178. PMC: 10150277. DOI: 10.1093/cid/ciad109. View

15.

Shahab M, Hayat C, Sikandar R, Zheng G, Akter S . In silico designing of a multi-epitope vaccine against Burkholderia pseudomallei: reverse vaccinology and immunoinformatics. J Genet Eng Biotechnol. 2022; 20(1):100. PMC: 9275536. DOI: 10.1186/s43141-022-00379-4. View

16.

Sutton K, Breen J, Russo T, Schultz L, Umland T . Crystal structure of 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase from the ESKAPE pathogen Acinetobacter baumannii. Acta Crystallogr F Struct Biol Commun. 2016; 72(Pt 3):179-87. PMC: 4774876. DOI: 10.1107/S2053230X16001114. View

17.

Uppalapati S, Sett A, Pathania R . The Outer Membrane Proteins OmpA, CarO, and OprD of Confer a Two-Pronged Defense in Facilitating Its Success as a Potent Human Pathogen. Front Microbiol. 2020; 11:589234. PMC: 7573547. DOI: 10.3389/fmicb.2020.589234. View

18.

Daina A, Michielin O, Zoete V . SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017; 7:42717. PMC: 5335600. DOI: 10.1038/srep42717. View

19.

Cerny M, Kalgutkar A, Obach R, Sharma R, Spracklin D, Walker G . Effective Application of Metabolite Profiling in Drug Design and Discovery. J Med Chem. 2020; 63(12):6387-6406. DOI: 10.1021/acs.jmedchem.9b01840. View