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 fie ld-based matching of a representative set of rigid conformers of three non- nucleoside HIV-1 reverse transcriptase inhibitors and solutions obtained fr om flexible matching of the same conformers is presented. In some cases, di fferent alignment solutions obtained from rigid matching converge to the sa me solution when conformational rigidity is relaxed, indicating that a redu ced set of conformers per molecule may be sufficient in many field-based si milarity studies. Furthermore, the results also indicate the importance of going beyond the pairwise similarity level to obtain consistent solutions i n flexible-matching studies. In this respect, the best conformationally fle xible multi-molecule alignment obtained is found to be in good agreement wi th 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.