CONFORMATIONAL SEARCHING IN ISIS/3D DATABASES

Three-dimensional structure databases, and their accompanying searching software, have been available for several years, both from commercial software vendors and by in-house development. Commercially available systems include MACCS-II/3D and ISIS/3D (MDL Information Systems, Inc.),Aladdin (Abbott Laboratories and Daylight Chemical Information Systems, Inc.), ChemDBS-3D (Chemical Design Ltd.), SYBYL/3DB Unity (Tripes Associates), and Catalyst (BioCad Corp.). With the exception of ChemDBS-3D and, most recently, SYBYL/3D Unity, these software products apply geometric searching algorithms to static 3D models. This is acceptable for relatively rigid structures but fails to take into account the inherent flexibility of many molecules of biological interest. Approaches to this problem have included the registration of multiple conformations (all products), conformational analysis at registration and search time (ChemDBS-3D), development of 3D queries that can accommodate limited flexibility in the target structures (MACCS-II/3D, ISIS/3D), and, most recently, application of the directed tweak approach (SYBYL/3DB Unity). This paper will discuss a new approach to the problem, implemented within the ISIS/3D software. The method uses a multilevel screening and constraint-fitting approach, applying torsional optimization with van der Waals energy contributions in the later stages. Methodology and examples are covered.