Structure Based Design of CYP51 Inhibitors

Structure based design has been widely used in many drug development programs. In parallel with the evolution of high performance computing systems and versatile molecular modeling programs, structure based drug design has become indispensible in many research areas. CYP51 is a proven therapeutic target for anti-fungal drugs. While anti-fungal drugs targeting CYP51 have a long history and a large pool of anti-fungal CYP51 inhibitor therapeutics are now available, structure based design of therapeutic agents targeting CYP51 has only recently been attempted, Here, we present structural features of CYP51 and its complexes formed with lanosterol, azole drugs, and specifically designed inhibitors. In particular, the first x-ray co-crystal structures of fungal CYP51 complexed with lanosterol and itraconazole are compared with co-crystal structures of other protozoal CYP51 enzymes. It is anticipated that comparative analyses of these structures, and other structures that emerge in coming years, will provide clear rationales to address issues in the development of CYP51 drug candidates such as drug resistant, selectivity against other human CYP enzymes, and diversity of CYP51 inhibitors.