Abstract
High-resolution single-crystal X-ray measurements of the monoclinic polymorph of bicalutamide and the aspherical atom databank approach have served as a basis for a reconstruction of the charge density distribution of the drug and its androgen receptor (AR) and albumin complexes. The contributions of various types of intermolecular interactions to the total crystal energy or ligand:AR energy were estimated. The cyan and amide groups secured the ligand placement in the albumin (Lys-137) and the AR binding pocket (Leu-704, Asn-705, Arg-752), and also determined the packing of the small-molecule crystals. The total electrostatic interaction energy on average was -230 kJ mol-1, comparable with the electrostatic lattice energy of the monoclinic bicalutamide polymorph. This is the result of similar distributions of electropositive and electronegative regions on the experimental and theoretical molecular electrostatic potential maps despite differences in molecular conformations. In general, bicalutamide interacted with the studied proteins with similar electrostatic interaction energies and adjusted its conformation and electrostatic potential to fit the binding pocket in such a way as to enhance the interactions, e.g. hydrogen bonds and π⋯π stacking.
Highlights
One of the most challenging problems in molecular biology is the search for the mechanism of the agonistic or antagonistic activities of genes related to the growth of tumour tissue
S—O bonds have a negative sign for r2(r) and the same was observed in several experimental charge density studies of inorganic compounds
The electrostatic lattice energy calculated by the exact potential and multipole model (EP/MM) method based on the experimental charge density was calculated to be À210.5 kJ molÀ1, which is very close to the averaged electrostatic interaction energy in the androgen receptor (AR) binding pocket, À198.9 kJ molÀ1
Summary
One of the most challenging problems in molecular biology is the search for the mechanism of the agonistic or antagonistic activities of genes related to the growth of tumour tissue. It is assumed that the activity of the agonists is affected by a geometric complementarity between the ligand guests and protein pocket hosts, and by the ability of the ligands to form stable supramolecular associates by means of specific hydrogen bonding and van der Waals interactions with the macromolecules The results of both X-ray and theoretical studies have shown that hydrogen bonds and van der Waals interactions are, at least, partially responsible for the ligand binding with the protein chain (Andrews et al, 1984; Carver et al, 1998; Freitas et al, 2010). Our work is focused on the evaluation of these quantities from high-resolution X-ray experiments and applications of these parameters to study the binding of the receptor to different sites
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