Atom type preferences, structural diversity, and property profiles of known drugs, leads, and nondrugs: a comparative assessment.

A new characterization of known drug, lead, and representative nondrug databases was performed taking into account several properties at the atomic and molecular levels. This characterization included atom type preferences, intrinsic structural diversity (Atom Type Diversity, ATD), and other well-known physicochemical properties, as an approach for rapid assessment of druglikeness for small molecule libraries. To characterize ATD, an elaborate united atom classification, UALOGP (United Atom Log P), with 148 atom types, was developed along with associated atomic physicochemical parameters. This classification also enabled an analysis of atom type and physicochemical property distributions (for calculated log P, molar refractivity, molecular weight, total atom count, and ATD) of drug, lead, and nondrug databases, a reassessment of the Ro5 (Rule of Five) and GVW (Ghose−Viswanadhan−Wendoloski) criteria, and development of new criteria and ranges more accurately reflecting the chemical space occupied by small molecule drugs. A relative druglikeness parameter was defined for atom types in drugs, identifying the most preferred types. The present work demonstrates that drug molecules are constitutionally more diverse relative to nondrugs, while being less diverse than leads.

Analysis of crystal structures of LXRbeta in relation to plasticity of the ligand-binding domain upon ligand binding.

Liver X receptors (LXRs) are a member of the nuclear hormone receptor superfamily of ligand activated transcription factors. LXRs have gained importance as therapeutic targets because of their involvement in many diseases. Analysis of the protein-ligand complexes of X-ray crystallography-derived structures revealed that residues His435 and Trp457 act as a switch that mediates ligand activation. These residues show conservation for main chain (phi, psi) in His435 and moderate movement for Trp457. His435 in Helix11 (H11) is conserved in relation to Trp457 in Helix12 (H12). This shows that some induced fit effect can be incorporated while designing ligands for activation of LXR with relation to Trp457 rather than that of His435. Similarly, main chain movement in Phe329 and Leu330 showed significant conformational mobility leading to flexibility in the ligand-binding domain (LBD) along with Arg319 which has a moderate movement in (phi and psi) angles. It is interesting to know that for some sequence-ligand complex crystallizations using different conditions show considerable main chain and side chain mobility indicating plasticity in LBD of LXRbeta. This study supports our understanding the relative movement of residues in the LBD of LXRs upon ligand binding which can provide insight for designing of LXRs modulators.