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We present empirical energy calculations on the binding of thyroxine analogs to the plasma protein prealbumin. The results of the calculations suggest a stronger binding affinity for the L isomer than the D, consistent with observed binding affinities. These calculations allow us to rationalize the significantly stronger binding of des-NH3+ than des-COO− analogs of the hormone to the protein.

Using a data set comprised of literature compounds and structure−activity data for cyclin dependent kinase 2, several pharmacophore hypotheses were generated using Catalyst and evaluated using several criteria. The two best were used in retrospective searches of 10 three-dimensional databases containing over 1 000 000 proprietary compounds. The results were then analyzed for the efficiency with which the hypotheses performed in the areas of compound prioritization, library prioritization, and library design. First as a test of their compound prioritization capabilities, the pharmacophore models were used to search combinatorial libraries that were known to contain CDK active compounds to see if the pharmacophore models could selectively choose the active compounds over the inactive compounds. Second as a test of their utility in library design again the pharmacophore models were used to search the active combinatorial libraries to see if the key synthons were over represented in the hits from the pharmaco...

Bands due to overtone and combination vibrational modes attributable to the imide grouping have been elucidated in the near-IR absorption spectra of small-ring cyclic imides, in which the grouping is in a cis, cis conformation. The spectra closely parallel the spectra of cis lactams except that two combination modes involving the carbonyl stretching fundamental, [ν(NH) + ν(CO)] and [2ν(C=O) + imide III], occur at higher wavenumbers in the imide spectra, reflecting the higher frequency at which this fundamental absorbs. This same factor results in a reversal in the wavenumber positions of the [2ν(CO) + imide III] and [ν(NH) + imide III] combination bands in the imide spectra relative to those in the lactam spectra. In addition, in-phase and out-of-phase vibrational coupling between the two carbonyl groups in the imides may compound the band due to the [ν(NH) + ν(CO)] combination mode. These three spectral characteristics serve to distinguish the imides from the lactams in the near-IR.

Dimethyl 2-methyl-5-(chloropyridin-2-yl)pyrrole-3,4-dicarboxylates in which the chlorine atom is substituted at different positions of the pyridine ring have widely varying biological properties. The 3-chloro analog (I) is a post-emergence and pre-emergence herbicide, the 4- and 5-chloro analogs (II, III) are post-emergence herbicides but not pre-emergence, and the 6-chloro analog (IV) is inactive. Computer graphic and molecular mechanics analyses of their molecular conformations showed that the 4- and 5-chloro analogs adopt a coplanar, intramolecularly hydrogen bonded conformation whereas the 3-chloro analog does not. High-level quantum mechanical calculations of the conformational preferences of related model systems were in agreement with these results. Based on this, II and III were predicted to have higher octanol/water partition coefficients relative to I, leading to higher soil binding and weaker xylem transport, hence their observed weaker pre-emergence activities. Experimental measurements of octanol/water partition coefficients, soil binding, and infrared hydrogen bonding studies verified these predictions. Molecular modeling techniques are usually used for designing compounds to fit enzyme active sites and designing putative receptor models. This study demonstrates the usefulness of these techniques for dealing with transport problems.

Using a data set comprised of literature compounds and structure-activity data for cyclin dependent kinase 2, several pharmacophore hypotheses were generated using Catalyst and evaluated using several criteria. The two best were used in retrospective searches of 10 three-dimensional databases containing over 1,000,000 proprietary compounds. The results were then analyzed for the efficiency with which the hypotheses performed in the areas of compound prioritization, library prioritization, and library design. First as a test of their compound prioritization capabilities, the pharmacophore models were used to search combinatorial libraries that were known to contain CDK active compounds to see if the pharmacophore models could selectively choose the active compounds over the inactive compounds. Second as a test of their utility in library design again the pharmacophore models were used to search the active combinatorial libraries to see if the key synthons were over represented in the hits from the pharmacophore searches. Finally as a test of their ability to prioritize combinatorial libraries, several inactive libraries were searched in addition to the active libraries in order to see if the active libraries produced significantly more hits than the inactive libraries. For this study the pharmacophore models showed potential in all three areas. For compound prioritization, one of the models selected active compounds at a rate nearly 11 times that of random compound selection though in other cases models missed the active compounds entirely. For library design, most of the key fragments were over represented in the hits from at least one of the searches though again some key fragments were missed. Finally, for library prioritization, the two active libraries both produced a significant number of hits with both pharmacophore models, whereas none of the eight inactive libraries produced a significant number of hits for both models.

Theoretical electronic structure calculations on the thyroid hormones and analogues, as well as model hormone--receptor interactions, have been carried out. These studies (a) support the concept that the 4'-OH group is a H-bond donor to the in vivo nuclear receptor and suggest that at the receptor this OH group is trans to the 3' (distal) substituent; (b) indicate that there is an important intramolecular interaction between 3' and 4' substituents, and those 3' substituents that most favor both 4' OH orientation trans to the 3' group and a more acidic OH group substantially increase binding and biological activity; and (c) support the concept that there is a direct correlation between the conformational free energy of the aromatic rings and biological activity.

We have performed molecular dynamics calculations for liquid water using the revised central force model potential truncated at various distances and using two sizes of system, in order to study the effect of system size and range of the potential on the calculated thermodynamic and structural properties and to compare the results with those obtained by Ewald summation. All calculations were performed for a cubic system using periodic boundary conditions. Provided the side of the cube is equal to or greater than twice the range of the potential, the thermodynamic properties and distribution functions, including an orientational distribution function, are insensitive to the size of the system, for fixed range. Provided the range of the potential is equal to or greater than 6 A, the thermodynamic energy and pressure are only slightly dependent on the range of the potential, to an extent that is, however, larger than that observed for dipolar hard spheres and the Stockmayer potential which do not have the tetrahedral structure similar to water. For potentials with ranges of 6 A or greater, the atom–atom distribution functions are very insensitive to the range, but the orientational correlations are very sensitive to the range, as had been observed many times in studies of dielectric properties of simulated fluids. A potential with a range of 6 A has thermodynamic and structural properties very similar to those of a longer ranged potential and similar to those obtained by Ewald summation. Use of such a model, which correctly describes interactions between nearest neighbors and next nearest neighbors but has no longer ranged forces, lead to significant increases in the speed of simulations.

We present a comparative analysis of an NMR experiment and molecular and harmonic dynamics simulations of an actinomycin D: d(ATGCAT)2 complex. A comparison of NOE measurements and 1/R6 weighted proton-proton distances confirm the general correctness of the Actinomycin D-DNA model proposed by Sobell. There are, however, some substantial differences between the proton-proton distances inferred from the NOE results and the molecular and harmonic dynamics simulations. The remaining discrepancies could either come from contributions of other conformations to the average properties of the complex or from uncertainties in the NMR distance analysis. An analysis of the molecular dynamics helix properties, sugar puckers, hydrogen bonding, rms fluctuations and torsional properties are qualitatively consistent with those from previous simulations, but the presence of an intercalated drug leads to some new structural and dynamical features.

Theoretical electronic structure calculations on the thyroid hormones and analogues, as well as model hormone--receptor interactions, have been carried out. These studies (a) support the concept that the 4'-OH group is a H-bond donor to the in vivo nuclear receptor and suggest that at the receptor this OH group is trans to the 3' (distal) substituent; (b) indicate that there is an important intramolecular interaction between 3' and 4' substituents, and those 3' substituents that most favor both 4' OH orientation trans to the 3' group and a more acidic OH group substantially increase binding and biological activity; and (c) support the concept that there is a direct correlation between the conformational free energy of the aromatic rings and biological activity.