A molecular-field-based similarity study of non-nucleoside HIV-1 reverse transcriptase inhibitors. 2. The relationship between alignment solutions obtained from conformationally rigid and flexible matching

An analysis of the relationship among alignment solutions obtained from field-based matching of a representative set of rigid conformers of three non-nucleoside HIV-1 reverse transcriptase inhibitors and solutions obtained from flexible matching of the same conformers is presented. In some cases, different alignment solutions obtained from rigid matching converge to the same solution when conformational rigidity is relaxed, indicating that a reduced set of conformers per molecule may be sufficient in many field-based similarity studies. Furthermore, the results also indicate the importance of going beyond the pairwise similarity level to obtain consistent solutions in flexible-matching studies. In this respect, the best conformationally flexible multi-molecule alignment obtained is found to be in good agreement with the relative binding geometry and orientation found experimentally from protein-ligand crystal structures. The rms separation between corresponding atoms in computed and 'experimental' sets of three inhibitor structures is 0.94 Angstrom.