Integrating medicinal chemistry, organic/combinatorial chemistry, and computational chemistry for the discovery of selective estrogen receptor modulators with Forecaster, a novel platform for drug discovery.

As part of a large medicinal chemistry program, we wish to develop novel selective estrogen receptor modulators (SERMs) as potential breast cancer treatments using a combination of experimental and computational approaches. However, one of the remaining difficulties nowadays is to fully integrate computational (i.e.

Pharmacophore screening of the protein data bank for specific binding site chemistry.

A simple computational approach was developed to screen the Protein Data Bank (PDB) for putative pockets possessing a specific binding site chemistry and geometry. The method employs two commonly used 3D screening technologies, namely identification of cavities in protein structures and pharmacophore screening of chemical libraries. For each protein structure, a pocket finding algorithm is used to extract potential binding sites containing the correct types of residues, which are then stored in a large SDF-formatted virtual library; pharmacophore filters describing the desired binding site chemistry and geometry are then applied to screen this virtual library and identify pockets matching the specified structural chemistry.

State-resolved dynamics of the CN(B2Sigma+) and CH(A2Delta) excited products resulting from the VUV photodissociation of CH3CN.

Fourier transform visible spectroscopy, in conjunction with VUV photons produced by a synchrotron, is employed to investigate the photodissociation of CH3CN. Emission is observed from both the CN(B2Sigma+-X2Sigma+) and CH(A2Delta-X2Pi) transitions; only the former is observed in spectra recorded at 10.2 and 11.

Dynamics of the CH(A2Delta) product from the reaction of C2H with O2 studied by Fourier transform visible spectroscopy.

The reaction C(2)H + O(2) --> CH(A(2)Delta) + CO(2) is investigated using Fourier transform visible emission spectroscopy. C(2)H radicals, produced by 193 nm photolysis of C(2)H(2), react with O(2) molecules at low total pressures to produce electronically excited CH(A(2)Delta). Observation of the CH(A(2)Delta-X(2)Pi) electronic emission to infer nascent rotational and vibrational CH(A(2)Delta) distributions provides information about energy partitioning in the CH(A(2)Delta) fragment during the reaction.

Light scattering of ultrafine silica particles by VUV synchrotron radiation.

Vacuum ultraviolet (VUV) light scattering from ultrafine silica particles is studied with an aerosol instrument recently established at the Advanced Light Source (ALS) in Berkeley. Silica particles, size-selected by a differential mobility analyzer, are introduced into vacuum through a set of aerodynamic lenses to form a particle beam. The scattered photons from the crossing area of the VUV synchrotron beam and particle beam are detected with a rotatable VUV photon detector.