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DRUG-GENE EXPRESSION PROFILES AND SYSTEMS BIOLOGY APPROACH TO IDENTIFY REPURPOSED DRUG CANDIDATES FOR TARGETING SCLEROSTIN IN PERI-IMPLANTITIS DISEASE.

DRUG-GENE EXPRESSION PROFILES AND SYSTEMS BIOLOGY APPROACH TO IDENTIFY REPURPOSED DRUG CANDIDATES FOR TARGETING SCLEROSTIN IN PERI-IMPLANTITIS DISEASE.

Dr.Pradeep Kumar Yadalam

Successful identification of a therapeutic strategy to treat patients with periimplantitis remains extremely important as post-implant bone degradation leads to implant failure and extreme bone loss. Given that the establishment of a new drug is quite expensive and time-consuming, the drug repurposing approach has come in handy. It helps to identify the experimental drugs that are beyond the purview of the initial clinical indication. In our current study, we propose a three-step drug repurposing approach in treating peri-implant bone defects and investigating the action of the FDA approved drugs to inhibit the key protein Sclerostin, involved in bone degradation. As the preliminary step, we differentiated the gene expression pattern in periimplantitis and dentate patients with their drug-induced profiles to identify the primary lead candidates. As the second step, we employed the computational biology approach to evaluate the protein-drug interaction and segregate the best hits among the identified lead compounds for sclerostin. Finally, the mode of action network for each candidate is established with the help of literature support, and the drug enrichment and pathway analysis are performed on the target genes in the network to evaluate the drug efficacy. This approach provided us with a drug interaction profile and specific genes and biomarkers to target bone mineralization in peri-implantitis. Thus, our three-step drug repurposing method is consistent with identifying the drug molecules with high efficacy and developing an efficient therapeutic strategy to treat peri-implantitis.

Posted by rsg2sec on

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.