An in silico approach for identification of lead compound as FtsZ inhibitor

• Published in: Molecular diversity 2024-12, Vol.28 (6), p.3937-3948
• Main Authors: Kifayat, Sumaiya, Almuqdadi, Haider Thaer Abdulhameed, Singh, Ravindra Pal, Singh, Mithilesh, Abid, Mohammad, Sanapalli, Bharat Kumar Reddy
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; Biochemistry; Biomedical and Life Sciences; Computer Simulation; Cytoskeletal Proteins - antagonists & inhibitors; Cytoskeletal Proteins - chemistry; Cytoskeletal Proteins - metabolism; Life Sciences; Ligands; Molecular Docking Simulation; Organic Chemistry; Original Article; Pharmacy; Polymer Sciences; Protein Binding; Proteins; Staphylococcus aureus - drug effects
• ISSN: 1381-1991; 1573-501X; 1573-501X
• DOI: 10.1007/s11030-023-10787-4

The remarkable conservation of the FtsZ among Gram-positive and Gram-negative bacteria, a crucial GTPase in bacterial cell division, has emerged as a promising antibacterial drug target to combat antibacterial resistance. There have been several coordinated efforts to develop inhibitors against FtsZ which can also serve as potential candidates for future antibiotics. In the present study, a natural product-like library (≈50,000 compounds) was employed to conduct HTVS against Staphylococcus aureus FtsZ protein (PDB Id: 6KVP). Additionally, molecular docking was carried out in two modes, SP and XP docking, using the Schrödinger suite. The glide scores of ligands obtained by XP docking were further summarized and compared with the control ligands (ZI1- co-crystal and PC190723—a compound undergoing clinical trial). Using the Prime-MM-GBSA approach, BFE calculations were performed on the top XP-scored ligands (≈598 compounds). These hits were also evaluated for ADMET parameters using the Qikprop algorithm, SwissADME, and in silico carcinogenicity testing using Carcinopred-El. Based on the results, ligand 4-FtsZ complex was considered for the 300 ns MDS analysis to get insights into its binding modes within the catalytic pocket of FtsZ protein. The analysis revealed that the amide linkage sandwiched between the triazole and 1-oxa-8-azaspirodecan-8-ium moiety (Val203) as well as the aminoethyl group present at 1st position on the triazole moiety (Leu209, Leu200, Asp210, and Ala202) were responsible for the FtsZ inhibitory activity, owing to their crucial interactions with key amino acid residues. Further, the complex also displayed good protein–ligand stability, ultimately predicting ligand 4 as a potent lead compound for the inhibition of FtsZ. Thus, our in silico findings will serve as a framework for in-depth in-vitro and in-vivo investigations encouraging the development of FtsZ inhibitors as a new generation of antibacterial agents. Graphical Abstract Graphical representation of in silico approach for identification of novel inhibitors against FtsZ