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The volume of distribution (VD) in humans of 179 known drug molecules (acids, bases, and neutrals) has been modeled using two biomimetic-binding measurements. The phospholipid binding (log K (IAM)) and the plasma protein binding (log K (HSA)) have been calculated from gradient HPLC retention times on immobilized artificial membrane (IAM) and on human serum albumin (HSA) columns, respectively. The log VD values showed good correlation with the compounds' relative binding to IAM and HSA as follows: log VD=0.44 log K (IAM)-0.22 log K (HSA)-0.66; n=179, r2=0.76, s=0.33, and F=272. It was also observed that positively charged molecules bind relatively more to IAM, while negatively charged ones bind more to HSA, in line with the empirical observation that bases tend to have a larger volume of distribution than acids. These results suggest that with the help of these two simple high throughput HPLC-based biomimetic binding measurements an important in vivo drug disposition property can be estimated for use in early drug discovery.

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Protein tyrosine kinases play a fundamental role in signal transduction pathways regulating a number of cellular functions such as cell growth, differentiation and cell death. Tyrosine kinases are, therefore attractive targets for the design of new therapeutic agents, not only against cancer, but also against many other diseases. Numerous tyrosine kinase inhibitors have been discovered by screening of plant extracts based on ethnopharmacological and chemotaxonomical knowledge. Specific screening approaches have led to the isolation of structurally distinct classes of inhibitors, including phenylpropanes, chalcones, flavonoids, coumarins, styrenes, quinones and terpenes. These natural inhibitors have served as valuable leads for further design and synthesis of more active analogues. Many of these inhibitors have also been used in probing the molecular and cellular mechanisms involved in the protein tyrosine kinase mediated signal transduction. In this review, plant-derived protein tyrosine kinase inhibitors and their synthetic analogues were systematically evaluated based on their plant origin, structure-activity relationship and anticancer efficacy.

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