Inhibition of lactate dehydrogenase C(4): The design, synthesis, and testing of ligands as an approach to male contraception.

摘要

Human lactate dehydrogenase C (LDHC₄), found in the spermatozoa and testis of the human male, presents an attractive target for male contraception due to its essential role in reproductive potency and sperm motility. Utilizing Composer, a protein homology modeling module of SYBYL, a model of human LDHC as well as the two other known human isozymes of LDH (LDHA₄ and LDHB₄) have been constructed. Comparison of these three structures revealed a high degree of similarity within the active substrate binding domain. Docking of known ligands with the LDHC homology model utilizing various virtual screening methods (DOCK4.0, FlexX, and molecular mechanics minimization) resulted in an absence of correlation between actual and predicted activity. The use of previously elucidated structure activity data has lead to the design of a series of 1,4-dihydropyridine and aryl analogs as potential selective inhibitors of LDHC₄. Using LDH isolated from mouse tissue and cloned human LDHC₄, these inhibitors were tested for activity against the LDH in the hopes of developing a potent, selective inhibitor for LDHC₄.