Surface plasmon resonance or SPR, is a biophysical method that provides kinetic information on biomolecular interactions, through measuring association and dissociation kinetics in real time. The applications of SPR to drug discovery are widespread, and this talk will focus on the interactions of drug molecules with serum proteins, rather than the more common study of candidates with the target protein of interest. The Phase I clinical PK profile of BMS-779788, an agonist for the LXRb receptor, showed an unexpectedly high level of plasma exposure, in contrast to relatively normal values seen in preclinical models in rat and dog. Specifically, low volume of distribution (Vd) and low clearance (CL) values were seen, consistent with tight binding in the plasma. A hypothesis was formulated that the clinical observation was due to tight binding of BMS-779788 to a major serum protein, either human serum albumin or human a1-acid glycoprotein (HAGP). Experimental methods including equilibrium binding and SPR were used to probe the hypothesis. The binding kinetics for BMS-779788, a second generation molecule BMS-852927, and various control compounds were analyzed by SPR using purified human serum albumin, and a1-acid glycoprotein from human, dog and rat. The data from equilibrium binding and SPR were consistent with high affinity binding of BMS-779788 to HAGP, but not to human serum albumin. SPR revealed the interaction was driven by a relatively slow rate of dissociation from human AGP. The compound showed relatively fast dissociation rates from rat and dog AGPs, as well as from human serum albumin. The kinetics of BMS-852927 dissociation from AGPs, in contrast, were relatively rapid, especially from HAGP, predicting preclinical PK to be predictive in a Phase I study, which was subsequently demonstrated.

Applications of SPR to drug discovery: Understanding LXRb agonist binding profile to two key serum proteins

254th National Meeting (2017)

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