Carboxamide group conformation in the nicotinamide and thiazole-4-carboxamide rings: implications for enzyme binding.
Ab initio computations (RHF/6-31G* parallel 3-21G*) were performed on the thiazole-4-carboxamide group found in the antitumor drug tiazofurin and its dehydrogenase-binding anabolite thiazole-4-carboxamide adenine dinucleotide (TAD). Results indicate that the carboxamide group is constrained in the conformation in which the amino group is cis-planar to the ring nitrogen. This finding is consistent with carboxamide conformations observed in crystal structures of the thiazole nucleosides. In contrast, ab initio computations on the nicotinamide and dihydronicotinamide rings found in the cofactors NAD+ and NADH indicate two stable conformations for the carboxamide group. This finding confirms previous computational studies and is consistent with results from a survey of the Cambridge Structural Database. Natural bond orbital analysis indicates that the low-energy carboxamide conformers of all three heterocycles are stabilized by a combination of electrostatic and charge transfer interactions. A survey of the Protein Data Bank indicates that the carboxamide group conformation in TAD is constrained to that favored by dehydrogenase-bound NAD(P)(H).
Department of Biophysics, University of Rochester Medical Center, New York 14642.
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D000227:Adenine Nucleotides / Q000737:chemistry*; D000577:Amides / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry*; D003461:Crystallography; D004791:Enzyme Inhibitors / Q000737:chemistry*; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D008968:Molecular Conformation; D009249:NADP / Q000737:chemistry; D009536:Niacinamide / Q000737:chemistry*; D012254:Ribavirin / Q000031:analogs & derivatives* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000227:Adenine Nucleotides; D000577:Amides; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009536:Niacinamide; D012254:Ribavirin; D009249:NADP; C038167:thiazole-4-carboxamide adenine dinucleotide; D007168:IMP Dehydrogenase; C033706:tiazofurin