182
11.5.3 Siderophore Biosynthesis Inhibitors
As the L-Ornithine N
5
-oxygenase, N
5
-transacetylase, N
2
-transacetylase and nonribosomal peptide synthetases play a crucial role in synthesizing the siderophores,
one can target these enzymes to overcome the fungal infection.
11.5.4 Siderophore Transport Inhibitors
A number of proteins are involved in the siderophore-mediated iron transport system,
which includes reductases (Fre1p–4p), permease-oxidase complex (Ftr1p and Fet3p),
Sit1p (also called Arn3p), Arn1p and Enb1p (Heymann et al. 2002; Heymann et al.
2000; Lesuisse et al. 2001; Philpott and Protchenko 2008; Yun et al. 2001; Yun et al.
2000). These proteins can be targeted in an attempt to find a better antifungal agent.
11.5.5 Computational Approaches
An inhibitor can be designed against the siderophore biosynthetic pathway enzymes
and siderophore transporter proteins by applying the principles of structure-based
drug designing and/or fragment-based drug designing. The inhibitor is designed in
a manner that it has complementary features with respect to the functional groups of
the active site residues (amino acids). Hence, they can bind with greater affinity and
thus can form a stable complex with the receptor. Similarly, the structure-based
pharmacophore can also be predicted for these catalytic enzymes and the predicted
pharmacophore can be searched against the chemical databases for suitable compounds as siderophore biosynthetic enzyme inhibitors. In contrast, competitive
inhibitors of the biosynthetic pathway enzymes can also be identified using the
shape and structural information of the enzyme substrates. By applying the shapebased and fingerprint-based similarity search, suitable competitive enzyme inhibitors can also be predicted from the chemical databases. In addition, the drug
repurposing approach can also be applied to predict the existing drugs with antifungal activity. This approach reduces the drug discovery cost to a greater extent. In
addition, the success rate in this approach is also higher than other approaches.
11.6 Conclusion
The recent outbreaks and emergence of multidrug-resistant fungal strains insists on
the need for newer antifungal agents. As iron is essential for most of the biological
processes, fungi have well-established iron acquisition mechanisms for its survival.
Siderophores play an essential role in these iron acquisition mechanisms. This chapter briefs siderophores as antifungal drug targets and discusses various computational approaches to design a novel and potent antifungal agents.
A. Shanmugam et al.
11.5.3 Siderophore Biosynthesis Inhibitors
As the L-Ornithine N
5
-oxygenase, N
5
-transacetylase, N
2
-transacetylase and nonribosomal peptide synthetases play a crucial role in synthesizing the siderophores,
one can target these enzymes to overcome the fungal infection.
11.5.4 Siderophore Transport Inhibitors
A number of proteins are involved in the siderophore-mediated iron transport system,
which includes reductases (Fre1p–4p), permease-oxidase complex (Ftr1p and Fet3p),
Sit1p (also called Arn3p), Arn1p and Enb1p (Heymann et al. 2002; Heymann et al.
2000; Lesuisse et al. 2001; Philpott and Protchenko 2008; Yun et al. 2001; Yun et al.
2000). These proteins can be targeted in an attempt to find a better antifungal agent.
11.5.5 Computational Approaches
An inhibitor can be designed against the siderophore biosynthetic pathway enzymes
and siderophore transporter proteins by applying the principles of structure-based
drug designing and/or fragment-based drug designing. The inhibitor is designed in
a manner that it has complementary features with respect to the functional groups of
the active site residues (amino acids). Hence, they can bind with greater affinity and
thus can form a stable complex with the receptor. Similarly, the structure-based
pharmacophore can also be predicted for these catalytic enzymes and the predicted
pharmacophore can be searched against the chemical databases for suitable compounds as siderophore biosynthetic enzyme inhibitors. In contrast, competitive
inhibitors of the biosynthetic pathway enzymes can also be identified using the
shape and structural information of the enzyme substrates. By applying the shapebased and fingerprint-based similarity search, suitable competitive enzyme inhibitors can also be predicted from the chemical databases. In addition, the drug
repurposing approach can also be applied to predict the existing drugs with antifungal activity. This approach reduces the drug discovery cost to a greater extent. In
addition, the success rate in this approach is also higher than other approaches.
11.6 Conclusion
The recent outbreaks and emergence of multidrug-resistant fungal strains insists on
the need for newer antifungal agents. As iron is essential for most of the biological
processes, fungi have well-established iron acquisition mechanisms for its survival.
Siderophores play an essential role in these iron acquisition mechanisms. This chapter briefs siderophores as antifungal drug targets and discusses various computational approaches to design a novel and potent antifungal agents.
A. Shanmugam et al.