In this section, we further ranked the seven potential drug targets identified from Section 3
on the basis of the interaction between each drug and its target. For the same drug dose, the best drug & target pair should return the highest effectiveness in regulating the dynamics of acute phase proteins. It was fortunate that the binding kinetics for the pair of imidazo-pyrrolopyridine and JAK was found in the literature (i.e.
, the Ki
value shown in Section 4.1
). However, no binding kinetic data were found for the other six drug targets identified in Section 3
, although data might exist in commercial database from pharmaceutical companies (which was not accessible by public). Since the value of Ki
for the other six drug targets was not available in literature, it was assumed in this section that these targets were bound by the drug with the same kinetics as the one for imidazo-pyrrolopyridine and JAK. Based upon this, simulations were performed to evaluate the effectiveness of each drug-target pair on regulating the secretion rates of the three acute phase proteins. The effectiveness was quantified by the maximum percentage change in the secretion rate of each acute phase protein upon the binding of the drug to each target (Figure 9
). The values of Ki
were kept the same as those used in Section 4.1
. The drug dose was set to 60 nM because the simulation result in Figure 7
implies that was a high enough concentration to suppress the fibrinogen secretion. The binding of the drug to each of gp80, JAK, and gp130 reduced the secretion rates of fibrinogen (by 74.4%, 71.0%, and 71.8%) and haptoglobin (by 44.5%, 4.2%, and 5.3%) but enhanced the production rate of albumin (by 22.9%, 1.7%, and 2.2%). The interaction from these drug-target pairs generally inhibited the acute phase response, especially in suppressing the secretion of fibrinogen. This can be explained by the fact that these three receptors played an important role in initiating both JAK-STAT and MAPK-C/EBPβ pathways. The binding of a drug to STATC inhibited the expression of fibrinogen (by 2.6%), slightly enhanced the section of haptoglobin (by 0.01%), and barely reduced the expression of albumin (by 0.006%). This made sense, as inhibition of STAT3C prevented the activation of nuclear STAT3 dimer and thus down-regulated the expression of fibrinogen. The deactivation of JAK-STAT pathway released some
complex to MAPK-C/EBPβ pathway for enhancing the production of haptoglobin. Therefore, the drug-STAT3C interaction only partially suppressed the acute phase response. The binding of the drug to Raf and C/EBPβi
enhanced the secretion rate of albumin (by 0.08% and 54.2%), but reduced the secretion rate of haptoglobin (by 0.5% and 72.6%). Since Raf and C/EBPβi
were the upstream components for the activation of nuclear C/EBPβ, inhibition of these two components by drugs down-regulated haptoglobin expression and restored albumin activation. The drugs binding to either Raf or C/EBPβi
only partially inhibited the acute phase response, as the secretion of fibrinogen was enhanced by 0.2% and 0.001% upon the drug binding. The drug-MEK pair showed similar effect on acute phase response as the drug-Raf or drug-C/EBPβi
pair, however, the effect from the drug-MEK pair was very limited (less than 0.001%). One potential reason for this was that the initial concentration of MEK (i.e.
, 41,667 nM) overwhelmed the drug dose (i.e.
, 60 nM) in this simulation.
Based upon the simulation result shown in Figure 9
, components gp80, gp130, and JAK were ranked as the top three drug targets because: (1) they had a noticeable effect on the secretion rates of all three acute phase proteins; and (2) they counteracted the acute phase response, while the others only partially do so. While it was assumed that the same Ki
was used for all the drugs in this study for screening drug targets, this assumption can be relaxed if kinetic data are available in the future.
Maximum change of the secretion rates of the three acute phase proteins upon the binding of a drug with the concentration of 60 nM to each of the selected seven drug targets.