Do Go Chasing Waterfalls: Enoyl Reductase (FabI) in Complex with Inhibitors Stabilizes the Tetrameric Structure and Opens Water Channels

Autor(es)

Maltarollo, Vinicius Goncalves ; Shevchenko, Ekaterina ; Lima, Igor Daniel de Miranda ; Cino, Elio A. ; Ferreira, Glaucio Monteiro ; Poso, Antti ; Kronenberger, Thales

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF CHEMICAL INFORMATION AND MODELING; v. 62, n. 22, p. 16-pg., 2022-11-07.

Resumo

The enzyme enoyl-ACP reductase (FabI) is the limiting step of the membrane's fatty acid biosynthesis in bacteria and a druggable target for novel antibacterial agents. The FabI active form is a homotetramer, which displays the highest affinity to inhibitors. Herein, molecular dynamics studies were carried out using the structure of FabI in complex with known inhibitors to investigate their effects on tetramerization. Our results suggest that multimerization is essential for the integrity of the catalytic site and that inhibitor binding enables the multimerization by stabilizing the substrate binding loop (SBL, L:195-200) coupled with changes in the H4/5 (QR interface). We also observed that AFN-1252 (naphtpyridinone derivative) promotes unique conformational changes affecting monomer-monomer interfaces. These changes are induced by AFN-1252 interaction with key residues in the binding sites (Ala95, Tyr146, and Tyr156). In addition, the analysis of water trajectories indicated that AFN-1252 complexes allow more water molecules to enter the binding site than triclosan and MUT056399 complexes. FabI-AFN-1252 simulations show accumulation of water molecules near the Tyr146/147 pocket, which can become a hotspot to the design of novel FabI inhibitors. (AU)

• Processo FAPESP: 21/11205-9 - Desenvolvimento de novos fármacos baseados na estrutura de proteínas essenciais para síntese e metabolismo do colesterol, integrando estudos genéticos e modelagem molecular de pacientes dislipidêmicos
• Beneficiário: Glaucio Monteiro Ferreira
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado