Roles for Structural Biology in the Discovery of Drugs and Agrochemicals Targeting Sterol 14α-Demethylases

Abstract

Antifungal drugs and antifungal agrochemicals have significant limitations. These include several unintended consequences of their use including the growing importance of intrinsic and acquired resistance. These problems underpin an increasingly urgent need to improve the existing classes of antifungals and to discover novel antifungals. Structural insights into drug targets and their complexes with both substrates and inhibitory ligands increase opportunity for the discovery of more effective antifungals. Implementation of this promise, which requires multiple skill sets, is beginning to yield candidates from discovery programs that could more quickly find their place in the clinic. This review will describe how structural biology is providing information for the improvement and discovery of inhibitors targeting the essential fungal enzyme sterol 14α-demethylase.

In Silico Designing of a Multitope Vaccine against Rhizopus microsporus with Potential Activity against Other Mucormycosis Causing Fungi

“…In the field of in silico drug design, docking studies are of great importance as they predict the possible complexes that may generate from the binding between a ligand and its respective receptor and the numerical value of the ligand–receptor binding energy provides an estimation of the affinity between the complex components [ 43 ]. Neutrophils have a vital role in combating mucormycosis and as a result of neutrophil spore interaction, excessive expression of toll-like receptor (TLR) occurs [ 44 ].…”

Emerging Trends in the Use of Topical Antifungal-Corticosteroid Combinations

“…In the endoplasmic reticulum (ER) of the fungal cell, both azole subclasses work with the same MoA; they interfere with ergosterol biosynthesis ( Figure 3 ). They inhibit the cytochrome P450 dependent enzyme lanosterol 14-α-demethylase (CYP51) by binding to its active site in a non-competitive manner [ 22 , 29 , 62 ]. CYP51 is present in the outer membrane of the ER and catalyses the removal of the methyl group at carbon 14 [ 22 , 29 , 62 ].…”

“…They inhibit the cytochrome P450 dependent enzyme lanosterol 14-α-demethylase (CYP51) by binding to its active site in a non-competitive manner [ 22 , 29 , 62 ]. CYP51 is present in the outer membrane of the ER and catalyses the removal of the methyl group at carbon 14 [ 22 , 29 , 62 ]. In simple terms, CPY51 is crucial to the conversion of lanosterol precursor into ergosterol [ 29 , 62 ].…”

“…CYP51 is present in the outer membrane of the ER and catalyses the removal of the methyl group at carbon 14 [ 22 , 29 , 62 ]. In simple terms, CPY51 is crucial to the conversion of lanosterol precursor into ergosterol [ 29 , 62 ]. The inhibition of CYP51 by azoles such as miconazole ( Figure 3 ) leads to the accumulation of eburicol and toxic 14-α-methylsterols, including 14-α-methyl-3,6-diol [ 63 , 64 ] which can disrupt the close packing of acyl chains of phospholipids and alter the function of the cell membrane-bound enzymes (e.g., enzymes of the mitochondrial electron transport chain) [ 57 ].…”

New azolyl-derivatives as multitargeting agents against breast cancer and fungal infections: synthesis, biological evaluation and docking study

“…In addition, Candida albicans 14ademethylase (CaCYP51; 5v5z) and carbonic anhydrase (CaNce103; 6uwg) enzymes were investigated as possible targets to explain the antifungal effects of this compound. Both the fungal enzymes were reported to be inhibited by azole-based compounds 24,25 .…”