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Virtual screening suggest potential affinity between Corynebacterium ulcerans essential proteins and inedited synthetic derivatives of tetraisoquinoline alkaloids

Virtual screening suggest potential affinity between Corynebacterium ulcerans essential proteins and inedited synthetic derivatives of tetraisoquinoline alkaloids

Luis Felipe de Morais Melo, Gustavo Andrew Mahon Mendes Pereira, Luis Cezar Rodrigues and Edson Luiz Folador

Corynebacterium ulcerans is aerobic, gram-positive bacteria that causes diphtheria, by infecting several hosts have a larger reservoir than the other causative agents. Considered reemergent, isolated cases due C. ulcerans diphtheria have increased even in immunized nations, highlighting the importance to seek new drugs and treatments. In previous work, we applied the interolog mapping method to generate the interactome, identifying the conserved hub proteins for 10 C. ulcerans strains, whose Database of Essential Genes (DEG) validation, COG classification and GO analysis, were confirmed the essentiality of 457 hub proteins, 351 having less than 30% identity against the host, being potential pharmacological targets. Here, we submitted the 351 non-host homologous hub proteins to Phyre2, resulting in 119 viable three-dimensional structure (more than 90% of the amino acids in Ramachandran plot favorable regions). Submitted to fpocket, 145 pockets with drugability score >= 0.5 were identified, which after being subjected to molecular docking in Autodock Vina against a library containing 42 inedited synthetic derivatives of tetraisoquinolinic alkaloid molecules resulted in 6,090 complex, 2,864 getting energy <= -6, considered relevant. The UvrABC system protein B, essential in the DNA repair process, formed the best complex with molecule23 reaching binding energy of -9.9, performing favorable interactions precisely with the protein residues binding to DNA, such as: hydrogen bonds (ARG379, LYS380 and SER166), Van der Waals interactions (ARG146, ASP376, ASP396, GLU122, GLU32, LYS134, MET372 and TYR116), pi-electron interactions (TYR119, TYR119 and TYR169), among others. Additionally, the molecule41 complexed with Bifunctional RNase H/acid phosphatase protein (-9.6); the molecule34 competes for the ADP binding site on Bifunctional protein (-9.5); the molecule20 competes for the uridina-difosfato-n-acetilglicosanima binding site on UDP-N-acetylglucosamine 1-carboxyvinyltransferase protein (-9.4). The results make it possible to understand the molecular binding mechanisms, enabling the rational optimization of molecules, reducing costs associated with synthesis and in-vitro or in-vivo tests.