Theoretical insight into the mechanism for the inhibition of the cysteine protease cathepsin B by 1,2,4-thiadiazole derivatives

Autor(es)

Angel Vega-Teijido, Mauricio ^[1] ; Maluf, Sarah El Chamy ^[2] ; Bonturi, Camila Ramalho ^[2] ; Sambrano, Julio Ricardo ^[2] ; Ventura, Oscar N. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Republica, Fac Quim, DETEMA, Computat Chem & Biol Grp CCBG, Montevideo 11800 - Uruguay

^[2] Univ Estadual Paulista, Dept Matemat, Grp Modelagem & Simulacao Mol GMSM, BR-17033360 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Journal of Molecular Modeling; v. 20, n. 6 JUN 2014.
• Citações Web of Science: 1

Resumo

Several cellular disorders have been related to the overexpression of the cysteine protease cathepsin B (CatB), such as rheumatic arthritis, muscular dystrophy, osteoporosis, Alzheimer's disease, and tumor metastasis. Therefore, inhibiting CatB may be a way to control unregulated cellular functions and prevent tissue malformations. The inhibitory action of 1,2,4-thiadiazole (TDZ) derivatives has been associated in the literature with their ability to form disulfide bridges with the catalytic cysteine of CatB. In this work, we present molecular modeling and docking studies of a series of eight 1,2,4-thiadiazole compounds. Substitutions at two positions (3 and 5) on the 1,2,4-thiadiazole ring were analyzed, and the docking scores were correlated to experimental data. A correlation was found with the sequence of scores of four related compounds with different substituents at position 5. No correlation was observed for changes at position 3. In addition, quantum chemistry calculations were performed on smaller molecular models to study the mechanism of inhibition of TDZ at the active site of CatB. All possible protonation states of the ligand and the active site residues were assessed. The tautomeric form in which the proton is located on N2 was identified as the species that has the structural and energetic characteristics that would allow the ring opening of 1,2,4thiadiazole. (AU)

• Processo FAPESP: 09/52189-4 - Teoria do funcional da densidade aplicada a compostos do tipo 2-tiopi ridina com cisteino-proteases.
• Beneficiário: Camila Ramalho Bonturi
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 09/52188-8 - Teoria do funcional da densidade aplicada ao estudo do mecanismo de inibicao de cisteino-proteases por ligantes derivados do 1,2,4-tidia zol
• Beneficiário: Sarah El Chamy Maluf
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica