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A computational approach is described that can predict the VD(ss) of new compounds in humans, with an accuracy of within 2-fold of the actual value. A dataset of VD values for 384 drugs in humans was used to train a hybrid mixture discriminant analysis-random forest (MDA-RF) model using 31 computed descriptors. Descriptors included terms describing lipophilicity, ionization, molecular volume, and various molecular fragments. For a test set of 23 proprietary compounds not used in model construction, the geometric mean fold-error (GMFE) was 1.78-fold (+/-11.4%). The model was also tested using a leave-class out approach wherein subsets of drugs based on therapeutic class were removed from the training set of 384, the model was recast, and the VD(ss) values for each of the subsets were predicted. GMFE values ranged from 1.46 to 2.94-fold, depending on the subset. Finally, for an additional set of 74 compounds, VD(ss) predictions made using the computational model were compared to predictions made using previously described methods dependent on animal pharmacokinetic data. Computational VD(ss) predictions were, on average, 2.13-fold different from the VD(ss) predictions from animal data. The computational model described can predict human VD(ss) with an accuracy comparable to predictions requiring substantially greater effort and can be applied in place of animal experimentation.

Possible functional differences between P-glycoproteins (P-gps) encoded by the human MDR1 and mouse mdr1 and mdr3 genes with respect to drug resistance profiles and sensitivity to known modulators have been investigated. For this, the three genes were introduced and overexpressed in the same cellular background, that of Chinese hamster LR73 ovary cells, and drug-resistant clones expressing comparable amounts of the corresponding P-gps were selected under the same conditions. Analysis of the specific drug resistance profiles encoded by each P-gp for colchicine, adriamycin, vinblastine, and actinomycin D revealed overlapping but distinct patterns of drug resistance for the three isoforms. While all three P-gps conferred levels of resistance to vinblastine that did not vary by more than 2.5-fold, each isoform could be clearly distinguished by its capacity to confer resistance to colchicine and actinomycin D. Likewise, the study of structurally related and unrelated P-gp modulators indicated strong isoform-specific differences in the capacity of individual modulators to abrogate vinblastine resistance in the corresponding mdr transfectants. The study of several disubstituted piperazine analogs indicated that minor chemical modifications of the linker region of this modulator had strong effects on the sensitivity profile of each isoform to the modulator. Together, these results indicate that the three P-gp isoforms analyzed have specific and distinguishable functional characteristics with respect to interactions with drugs and modulators. These findings also suggest that P-gp positive murine transplantable tumors should be used with caution in the design and in vivo testing of novel P-gp modulators to be used to reverse multidrug resistance to tumor cells expressing human MDR1.

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Figure 7. Energy requirements for the insertion of formaldehyde into the Co-H bond of ~*-HCO(CO)~-H~CO. All energies are in kJ/mol. The numbers in brackets represent the activation energies for the reaction in the direction of the arrows. The numbers without brackets stand for the energy difference between two isomers, where a positive value indicates that the resulting complex is higher in energy.activation energy of only 55 kJ/mol. As indicated above this route might not produce much methanol, since the migratory shift of the hydroxymethyl group to a carbonyl ligand is, in analogy to the alkyl reaction, a very facile process. VI. Summary and ConclusionsWe have investigated here the geometries of the *-complexes that result from an interaction between formaldehyde and the coordinatively unsaturated cobalt complex HCO(CO)~. Furthermore, the insertion of the coordinated formaldehyde group into the Co-H bond was also studied by determining the geometries of some of the insertion products as well as by evaluating the energy profile of the insertion mechanism by a linear transit procedure.The migratory insertion of formaldehyde into the Co-H bond was shown to produce stable methoxy or hydroxymethyl intermediates. However, the methoxy complexes were 25 to 40 kJ/mol lower in energy. The energy difference was traced to the stronger Co-0 bond of the methoxy ligand. Both types of compounds were stabilized by the formation of an agostic interaction between the shifted hydride and the cobalt center. The migration of the hydride ligand to the carbon atom of the complexes aldehyde molecule was found to have a reaction enthalpy, AE, of 6 kJ/mol and an activation barrier, AE', of less than 5 kJ/mol. These values parallel the results of the ethylene insertion and underline the similarity of the two molecular systems. The alternative process where the hydride ligand migrates to the oxygen atom of the H2C0 group was somewhat disfavored by an endothermicity of 40 kJ/mol and an activation barrier of 15 kJ/mol. However, the energy requirements of the later process are small enough such that both insertion modes are operative under catalytic conditions where the formation of the methoxy intermediate is favored over the hydroxymethyl analogue. The energetics for the insertion process is summarized in Figure 7. Acknowledgment.Abstract: A molecular dynamics (MD) simulation was performed on the hydrated decapeptide Alalo~C50H20 under periodic boundary conditions. The initial configuration of the peptide was a canonical right-handed a-helix. Over the course of the MD trajectory, the helix is overall intact and dynamically stable, except for one position in which incipient helix destabilization is observed. The helix hydrogen bond at this position was first destabilized transiently for -10 ps. Some 35 ps later, a persistent destabilization occurred. Analysis reveals that the helix destabilizations are both accompanied by water insertion in a manner consistent with that recently proposed by Sundaralingan and Sekharudul based on a survey of ...

We report herein a theoretical calculation of the ion atmosphere contribution to the free energy of association for a protein-DNA complex based on Monte Carlo computer simulations and thermodynamic perturbation theory. The system considered is the dimer of the amino-terminal fragment of the Xcl repressor in a complex with a 17 base pair oligonucleotide of DNA, based on the crystal structure of Pabo and Sauer. Only the movements of the small ions (sodium and chloride ions) are considered explicitly, with solvent water modeled as a dielectric continuum (a "primitive model"). The free energies are determined as a function of both distance of separation between the protein and the DNA, each of which is fixed in its respective crystal geometry, and ionic strength at a temperature of 298 K. Results of our simulations indicate that the ion atmosphere contribution to the free energy of association is favorable only at short distances of separation and is at a maximum when the protein approaches the DNA from a distance of ~7 A. This distance corresponds to the radius of the shroud of condensed counterions around B-DNA. At larger distances of separation between the protein and the DNA, the uncondensed diffuse ionic cloud opposes complexation. The effect known as "counterion release" in the context of DNA-ligand association appears to be short-ranged and a property of the condensed counterions only.

High-throughput file screening against inhibition of human lung PDE4 led to the discovery of 3-ethyl-1-(4-fluorophenyl)-6-phenyl-7-oxo-4, 5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (11) as a novel PDE4 inhibitor. Subsequent SAR development, using an eosinophil PDE assay, led to analogues up to 50-fold more potent than 11 with IC50 values of 0.03-1.6 microM. One such compound, CP-220,629 (22) (IC50 = 0.44 microM), was efficacious in the guinea pig aerosolized antigen induced airway obstruction assay (ED50 2.0 mg/kg, po) and demonstrated a significant reduction in eosinophil (55%), neutrophil (65%), and IL-1beta (82%) responses to antigen challenge in atopic monkeys (10 mg/kg, po).