Database Searching for Compounds with Similar Biological Activity Using Short Binary Bit String Representations of Molecules

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Abstract
In an effort to identify biologically active molecules in compound databases, we have investigated similarity searching using short binary bit strings with a maximum of 54 bit positions. These “minifingerprints” (MFPs) were designed to account for the presence or absence of structural fragments and/or aromatic character, flexibility, and hydrogen-bonding capacity of molecules. MFP design was based on an analysis of distributions of molecular descriptors and structural fragments in two large compound collections. The performance of different MFPs and a reference fingerprint was tested by systematic “one-against-all” similarity searches of molecules in a database containing 364 compounds with different biological activities. For each fingerprint, the most effective similarity cutoff value was determined. An MFP accounting for only 32 structural fragments showed less than 2% false positive similarity matches and correctly assigned on average ∼40% of the compounds with the same biological activity to a query molecule. Inclusion of three numerical two-dimensional (2D) molecular descriptors increased the performance by 15%. This MFP performed better than a complex 2D fingerprint. At a similarity cutoff value of 0.85, the 2D fingerprint totally eliminated false positives but recognized less than 10% of the compounds within the same activity class.

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