selectivity. The amino acid residue Tyr Hs 147 form direct or indirect hydrogen bond
with His Hs 56 which moves the d nitrogen of His Hs 56 away from the inhibitor
binding site (Fig. 15). In case of PfDHODH, Tyr Hs 147 is replaced by Cis Pf 276
which cannot form hydrogen bond with His Pf 185, thus directing the d nitrogen
toward the inhibitor binding site forming a direct hydrogen bond with the inhibitor.
3.6.4 N-Alkyl-5-(1H-Benzimidazol-1-yl)Thiophene-2-Carboxamide
Compounds belonging to this class were designed based on the high-throughput
screening studies from Genzyme library, by Patel et al. [80a]. In this study, 208,000
compounds were screened for PfDHODH inhibitory activity. Thirty-eight compounds from this library were identified for showing PfDHODH inhibition in
Fig. 15 Overlapped N-terminal of PfDHODH (green) and HsDHODH (magenta) showing
important amino acids residues important for selectivity
Fig. 16 Structural modification of thiophene derivatives, toward optimization of PfDHODH
activity using SBDD approach
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S. Bhagat et al.
with His Hs 56 which moves the d nitrogen of His Hs 56 away from the inhibitor
binding site (Fig. 15). In case of PfDHODH, Tyr Hs 147 is replaced by Cis Pf 276
which cannot form hydrogen bond with His Pf 185, thus directing the d nitrogen
toward the inhibitor binding site forming a direct hydrogen bond with the inhibitor.
3.6.4 N-Alkyl-5-(1H-Benzimidazol-1-yl)Thiophene-2-Carboxamide
Compounds belonging to this class were designed based on the high-throughput
screening studies from Genzyme library, by Patel et al. [80a]. In this study, 208,000
compounds were screened for PfDHODH inhibitory activity. Thirty-eight compounds from this library were identified for showing PfDHODH inhibition in
Fig. 15 Overlapped N-terminal of PfDHODH (green) and HsDHODH (magenta) showing
important amino acids residues important for selectivity
Fig. 16 Structural modification of thiophene derivatives, toward optimization of PfDHODH
activity using SBDD approach
204
S. Bhagat et al.