Table 3. Thermodynamic Study of DHODH–Inhibitor Interactionsa.
PfDHODH |
rat DHODH |
||||||
---|---|---|---|---|---|---|---|
inhibitor | LogD | Kd μM (1σ) | ΔH kcal/mol | –TΔS kcal/mol | Kd μM (1σ) | ΔH kcal/mol | –TΔS kcal/mol |
8 | 3.55 | 0.17 (0.11–0.26) | –10 (−12 to −9.8) | 1.5 | nd | nd | nd |
5 | 4.05 | 0.027 (0.010–0.063) | –8.3 (−9.2 to −7.5) | –2.2 | nd | nd | nd |
10 | 4.25 | 0.0098 (0.0061–0.015) | –9.0 (−9.3 to −8.7) | –2.1 | nd | nd | nd |
11 | 4.46 | 0.0051 (0.0015–0.016) | –8.1 (−8.8 to −7.5) | –3.3 | 0.048 (0.0084–0.143) | –2.1 (−2.5 to −1.9) | –8.0 |
6 | 5.01 | 0.0096 (0.0040–0.019) | –6.5 (−6.9 to −6.2) | –4.5 | CNC | –1.6 (−1.8 to −1.5) | CNC |
Studies were performed at 303 K. The 1σ confidence interval is displayed in parentheses for three independent experiments. The PfDHODHΔ384–413 expression construct was used for the study. ND, not determined. CNC, could not calculate because the sharpness of the transition prevented an accurate determination of these values. For the free energy of binding, ΔG = ΔH – TΔS.