Experimental high-throughput screening analysis performed over 4000 natural
compounds recognized three new molecules, that includes Harmine, as selective
inhibitor of PfHSP90 [15]. Molecular docking and molecular dynamics analysis of
7-azaindole class of compounds (IND311 and IND31119) (Fig. 1) bound to
PfHSP90 active site have reported that the enzyme hydrophobic cavity is occupied
by the side chains present at first and second position of IND31119 [6b]. The side
chain of Asn37 residue forms two hydrogen bonds with secondary amine present at
position 5 and carbonyl of amide present at position 3 of IND31119. The 7th
position of IND31119 forms water-mediated hydrogen bond with Asn92 residue
and there was another Ile96 residue which also interacts with structural water
molecule. All these structural water molecules are conserved in enzyme active site
[13b]. An in vitro study demonstrated that Geldanamycin exhibits inhibitory action
on parasitic Hsp90 (with IC 50 of 20 nM) [16]. The 7-azaindole (i.e., IND3) and
several other its derivatives (i.e., IND31119 and IND311) possess in vitro and in
silico selective antimicrobial activity against PfHSP90. In 2018, Posfai et al.
reported in vitro inhibitory activity of indazol-4(5H)-one class of compounds i.e.
SNX-2112 (with K i 5.9 nM) and Harmine (with K i 27,000 nM) on PfHSP90 target
[17]. The molecular dynamics simulations performed on PfHsp90, human Hsp90,
and mutated PfHsp90 indicated that human Hsp90 and mutated Hsp90 have more
flexibility as compared to PfHsp90 [6b].
Fig. 1 Structure of PfATP-dependent heat shock protein 90 inhibitors
Structure-Based Design of PfDHODH Inhibitors …
181
compounds recognized three new molecules, that includes Harmine, as selective
inhibitor of PfHSP90 [15]. Molecular docking and molecular dynamics analysis of
7-azaindole class of compounds (IND311 and IND31119) (Fig. 1) bound to
PfHSP90 active site have reported that the enzyme hydrophobic cavity is occupied
by the side chains present at first and second position of IND31119 [6b]. The side
chain of Asn37 residue forms two hydrogen bonds with secondary amine present at
position 5 and carbonyl of amide present at position 3 of IND31119. The 7th
position of IND31119 forms water-mediated hydrogen bond with Asn92 residue
and there was another Ile96 residue which also interacts with structural water
molecule. All these structural water molecules are conserved in enzyme active site
[13b]. An in vitro study demonstrated that Geldanamycin exhibits inhibitory action
on parasitic Hsp90 (with IC 50 of 20 nM) [16]. The 7-azaindole (i.e., IND3) and
several other its derivatives (i.e., IND31119 and IND311) possess in vitro and in
silico selective antimicrobial activity against PfHSP90. In 2018, Posfai et al.
reported in vitro inhibitory activity of indazol-4(5H)-one class of compounds i.e.
SNX-2112 (with K i 5.9 nM) and Harmine (with K i 27,000 nM) on PfHSP90 target
[17]. The molecular dynamics simulations performed on PfHsp90, human Hsp90,
and mutated PfHsp90 indicated that human Hsp90 and mutated Hsp90 have more
flexibility as compared to PfHsp90 [6b].
Fig. 1 Structure of PfATP-dependent heat shock protein 90 inhibitors
Structure-Based Design of PfDHODH Inhibitors …
181