Activity Prediction

In drug discovery, researchers are not only interested in detecting

active molecules, but also in determining the biological activity
observed in a particular molecule. At the same time, it is useful to
identify the most representative subset of molecular descriptors to
help determine the attributes required in drug design. Due to the
flexibility of the molecular structure, a molecule may adopt a wide
range of conformers and identifying the bioactive conformers is very
important for understanding the recognition mechanism between small
molecules and proteins, which is crucial in drug discovery and
development.

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with several methods. Our advanced techniques and experienced
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 Multiple-instance Learning

Multiple-instance learning (MIL) is a machine learning method capable

of predicting bioactive conformers by using a variant of supervised
learning. In the MIL framework, each instance is recognized as a
feature vector, which commonly resides in the high-dimensional
feature space. The high dimensionality may offer significant
information for learning tasks, but at the same time, it may also
include a great deal of irrelevant or redundant features, which might
negatively affect learning performance. So, reducing the
dimensionality of data is the priority to facilitate the classification task
and improve the interpretability of the model. By using MIL, it is
possible to predict the contributions of individual conformers for each
molecule and identify the putative bioactive conformer. The unique
characteristics of MIL make it very useful for the pursuit of biologically
significant conformers. In the context of drug activity prediction, the
observed biological activity is associated with a single molecule
 without knowing which conformers are responsible. Furthermore, a
molecule is biologically active only if at least one of its conformers is
responsible for the observed bioactivity, and the molecule is inactive if
none of its conformers is responsible. As shown in Fig. 1., M 1, M2,
M3 and M4 represent the molecules, which are circled by dashed lines.
Molecules 2, 3, and 4 have biological activity since they have at least
one bioactive conformer, whereas molecule 1 is inactive since none of
its conformers is bioactive.

Fig. 1. Cartoon representation of the relationship between molecules and conformers.

 Probabilistic approaches

The most appropriate approaches in activity prediction are based on

the theory of probability. Generally, virtual screening method is used
for selecting hits with single required activity, while the final aim of
pharmaceutical R&D is identifying safe and potent lead. To overcome
this problem, a method has been developed for prediction of many
kinds of biological activity simultaneously based on the structural
formula of chemical compound, which is realized in PASS (Prediction
of Activity Spectra for Substance). PASS is a computer program that
can predict numerous pharmacotherapeutic effects, mechanisms of
action, interaction with the metabolic system, and specific toxicity for
 drug-like molecules with reasonable accuracy on the basis of their
structural formulae.

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Reference

1. Fu, G.; et al. Implementation of multiple-instance learning in drug activity

prediction. BMC bioinformatics, 2012, 13(15): S3