Navigating the chemical space of ENR Inhibitors : a comprehensive analysis

Kuralt, Vid (avtor), Frlan, Rok (avtor)

Antimicrobial resistance is a global health threat that requires innovative strategies against drug-resistant bacteria. Our study focuses on enoyl-acyl carrier protein reductases (ENRs), in particular FabI, FabK, FabV, and InhA, as potential antimicrobial agents. Despite their promising potential, the lack of clinical approvals for inhibitors such as triclosan and isoniazid underscores the challenges in achieving preclinical success. In our study, we curated and analyzed a dataset of 1412 small molecules recognized as ENR inhibitors, investigating different structural variants. Using advanced cheminformatic tools, we mapped the physicochemical landscape and identified specific structural features as key determinants of bioactivity. Furthermore, we investigated whether the compounds conform to Lipinski rules, PAINS, and Brenk filters, which are crucial for the advancement of compounds in development pipelines. Furthermore, we investigated structural diversity using four different representations: Chemotype diversity, molecular similarity, t-SNE visualization, molecular complexity, and cluster analysis. By using advanced bioinformatics tools such as matched molecular pairs (MMP) analysis, machine learning, and SHAP analysis, we were able to improve our understanding of the activity cliques and the precise effects of the functional groups. In summary, this chemoinformatic investigation has unraveled the FAB inhibitors and provided insights into rational antimicrobial design, seamlessly integrating computation into the discovery of new antimicrobial agents.

• Jezik: Angleški jezik
• Ključne besede: antibacterial drug development, enoyl-acyl carrier protein reductases, ENR inhibitors, antibiotic resistance, Fab, InhA, bioinformatical analysis
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2024
• Št. strani: 27 str.
• Številčenje: Vol. 13, iss. 3, art. 252
• PID: 20.500.12556/RUL-167908
• UDK: 615.015.8
• ISSN pri članku: 2079-6382
• DOI: 10.3390/antibiotics13030252
• COBISS.SI-ID: 229600771
• Datum objave v RUL: 20.03.2025

Gradivo je del revije

• Naslov: Antibiotics
• Skrajšan naslov: Antibiotics
• Založnik: MDPI
• ISSN: 2079-6382
• COBISS.SI-ID: 522975769

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: razvoj antibakterijskih zdravil, enoil-acil nosilne proteinske reduktaze, zaviralci ENR, odpornost na antibiotike, Fab, InhA, bioinformatska analiza, rezistenca

Projekti

• Financer: ARIS - Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije
• Številka projekta: P1-0208
• Naslov: Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin