Novel insights for dihydroorotate dehydrogenase class 1A inhibitors discovery.
The enzyme dihydroorotate dehydrogenase (DHODH) has been suggested as a promising target for the design of trypanocidal agents. We report here the discovery of novel inhibitors of Trypanosoma cruzi DHODH identified by a combination of virtual screening and ITC methods. Monitoring of the enzymatic reaction in the presence of selected ligands together with structural information obtained from X-ray crystallography analysis have allowed the identification and validation of a novel site of interaction (S2 site). This has provided important structural insights for the rational design of T. cruzi and Leishmania major DHODH inhibitors. The most potent compound (1) in the investigated series inhibits TcDHODH enzyme with Kiapp value of 19.28 μM and possesses a ligand efficiency of 0.54 kcal mol(-1) per non-H atom. The compounds described in this work are promising hits for further development.
Cheleski
Juliana
J
Grupo de Estudos em Química Medicinal de Produtos Naturais, NEQUIMED-PN, Instituto de Química de São Carlos, Universidade de São Paulo, Av. Trabalhador Sancarlense 400, 13560-970, São Carlos-SP, Brazil.
Rocha
Josmar R
JR
Pinheiro
Matheus P
MP
Wiggers
Helton José
HJ
da Silva
Albérico B F
AB
Nonato
Maria C
MC
Montanari
Carlos A
CA
D000595:Amino Acid Sequence; D055162:Biocatalysis; D019295:Computational Biology; D018360:Crystallography, X-Ray; D000090722:Dihydroorotate Dehydrogenase; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D018320:Leishmania major / Q000201:enzymology; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000201:enzymology
D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D008024:Ligands; D044925:Oxidoreductases Acting on CH-CH Group Donors