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1.  The composite solubility versus pH profile and its role in intestinal absorption prediction 
AAPS PharmSci  2003;5(1):35-49.
The purpose of this study was to examine absorption of basic drugs as a function of the composite solubility curve and intestinally relevant pH by using a gastrointestinal tract (GIT) absorption simulation based on the advanced compartmental absorption and transit model. Absorption simulations were carried out for virtual monobasic drugs having a range of pKa, log D, and dose values as a function of presumed solubility and permeability. Results were normally expressed as the combination that resulted in 25% absorption. Absorption of basic drugs was found to be a function of the whole solubility/pH relationship rather than a single solubility value at pH 7. In addition, the parameter spaces of greatest sensitivity were identified. We compared 3 theoretical scenarios: the GIT pH range overlapping (1) only the salt solubility curve, (2) the salt and base solubility curves, or (3) only the base curve. Experimental solubilities of 32 compounds were determined at pHs of 2.2 and 7.4, and they nearly all fitted into 2 of the postulated scenarios. Typically, base solubilities can be simulated in silico, but salt solubilities at low pH can only be measured. We concluded that quality absorption simulations of candidate drugs in most cases require experimental solubility determination at 2 pHs, to permit calculation of the whole solubility/pH profile.
PMCID: PMC2751472  PMID: 12713276
GIT; absorption simulation; pH solubility curve; BCS; solid-state properties; solubility screening
2.  Three-dimensional structure of fibrolase, the fibrinolytic enzyme from southern copperhead venom, modeled from the x-ray structure of adamalysin II and atrolysin C 
AAPS PharmSci  2001;3(2):78-90.
The fibrinolytic enzyme from southern copperhead snake venom, fibrolase, contains 1 mole of zine per mole of protein, belongs to the major family of metalloproteinases known as the metzincins, and has been shown to degrade fibrin clots in vitro and in vivo. The purpose of this study was to develop a 3-dimensional model of fibrolase to investigate the geometry of conserved and variable sequences between members of the snake venom metalloproteinases. When compared to atrolysin C (form D) or adamalysin II (metzincins with completely different substrate specificity), fibrolase has approximately 60% overall sequence identity and nearly 100% sequence similarity in the active site. We used the crystal structure of adamalysin II to build a 3-dimensional homology model of fibrolase. Three disulfide bonds were constructed (the highly conserved disulfide bond [118–198] was maintained from the adamalysin II structure and 2 new disulfide bonds were introduced between residues 158–182 and 160–165). We used Sculpt 2.5 and HyperChem 5.0 to “dock” a substrate fragment octapeptide (HTEKLVTS), and a water molecule into the active site cleft. We calculated the differential average homology profile for fibrolase compared to 8 hemorrhagic and 5 nonhemorrhagic metzincins. We then determined the sequence regions that might be responsible for their substrate specificity. Our 3-dimensional homology model shows that the variable sequences lie on the periphery of the identified active site region containing the His triangle; this indicates that substrate specificity may depend on surface residues that are not directly associated with the active site.
PMCID: PMC2779553  PMID: 11741267
Fibrolase; Metzincin; Homology Model; Substrate Specificity; Docking; Differential Average Homology

Results 1-2 (2)