A genetic algorithm for structure-based de novo design

Genetic algorithms have properties which make them attractive in de novo drug design. Like other de novo design programs, genetic algorithms require a method to reduce the enormous search space of possible compounds. Most often this is done using information from known ligands. We have developed the ADAPT program, a genetic algorithm which uses molecular interactions evaluated with docking calculations as a fitness function to reduce the search space. ADAPT does not require information about known ligands. The program takes an initial set of compounds and iteratively builds new compounds based on the fitness scores of the previous set of compounds. We describe the particulars of the ADAPT algorithm and its application to three well-studied target systems. We also show that the strategies of enhanced local sampling and re-introducing diversity to the compound population during the design cycle provide better results than conventional genetic algorithm protocols.     

KINETIC STUDIES OF THE TWO LIGHT REACTIONS IN PHOTOSYNTHESIS

Abstract— The decay kinetics of the photo-induced absorbance changes in red and green algae are very sensitive to the wavelength of the actinic light. A four to tenfold increase in half-decay time is noted in going from short wavelength (550–650 mμ) to long wavelength (> 700 mμ) excitation. The slow decay rates produced by long wavelength light can be enhanced with a steady background of short wavelength light. A relationship between initial decay rates and O₂ evolution rates is described. This relationship allows a direct correspondence between these spectroscopic studies and the 'red-drop' and 'enhancement' experiments of Emerson.     

The proton affinity of proline analogs using the kinetic method with full entropy analysis

The proton affinity of proline analogs, L-azetidine-2-carboxylic acid (Aze), L-proline (Pro), and L-pipecolic acid (Pip), have been measured using the Armentrout modification of the extended kinetic method in a quadrupole ion trap instrument. Experimental values of 223.0 +/- 1.5, 224.9 +/- 1.6, and 225.6 +/- 1.6 kcal/mol have been determined for the 298K proton affinities of Aze, Pro, and Pip respectively. High level theoretical calculations using both MP2 and B3LYP methods at a variety of basis sets were carried out in order to give theoretical predictions for the 298 K proton affinity and gas phase basicity of all three analogs. Recommended values for the gas phase basicity and proton affinity for proline based on our work and other recent determinations are 216 +/- 2 and 224 +/- 2 kcal/mol.     

CombiDOCK: Structure-based combinatorial docking and library design

We have developed a strategy for efficiently docking a large combinatorial library into a target receptor. For each scaffold orientation, all potential fragments are attached to the scaffold, their interactions with the receptor are individually scored and factorial combinations of fragments are constructed. To test its effectiveness, this approach is compared to two simple control algorithms. Our method is more efficient than the controls at selecting best scoring molecules and at selecting fragments for the construction of an exhaustive combinatorial library. We also carried out a retrospective analysis of the experimental results of a 10×10×10 exhaustive combinatorial library. An enrichment factor of approximately 4 was found for identifying the compounds in the library that are active at 330 nM.     

Preservation of Immunoreactivity in the Photolabeling of the B72.3 Human Antibody

Abstract— A mild and efficient method of linking a dihydroflavin to the C-17 carboxylic acid side chain of protochlorophyllide, without degradation of the sensitive E ring or loss of magnesium, is described. The appended dihydroflavin was shown to quench the fluorescence of protochlorophyllide. In contrast, a dihydronicotinamide moiety was unable to effect fluorescence quenching. The relevance of these findings to a possible mechanism of action of the enzyme protochlorophyllide reductase is discussed.     

Semi-empirical corrections to the mixing coefficients for the diatomics-in-molecules method

The diatomics-in-molecules (DIM) method requires information about the wavefunction (i.e. mixing coefficients) and the energy of various states of diatomic fragments. We show here that, if the diatomic energy is obtained from experiment, then it is also important to correct the mixing coefficients by making use of experimental atomic state energies. This point is illustrated by application to the OH⁺(³Σ^?) state manifold.     

A diatomics-in-molecules model for singly-ionized argon clusters

A DIM model using ab initio input for the diatomic interactions predicts a collinear bound Ar₃ ⁺ molecule (in agreement with ab initio calculations) and stable clusters Ar_n ⁺ consisting of an Ar₃ ⁺ ion embedded in (n?3) neutral atoms. These results support existing theories that dynamical size selection may be more relevant in interpreting experimental results than the relative stabilities of clusters in their minimum energy configurations.