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Template Matching

Template Matching

General remarks

In certain instances it may be useful replace a section of a small molecule by a new entity. This may be the case when a ligand to a protein consists of a central template decorated with a set of substituents that provide binding functionality to the protein. It may be possible that the substituents are not able to assume an optimal binding conformation due to geometrical constraints imposed by the template, or that the template is unsuited for any kind of reason. For such cases Moloc provides two types of functionality.
Firstly, soft-subset minimization allows the substituents to explore their optimal binding conformation by treating the template atoms as a yielding set with reduced force-field parameter values.
Secondly, a set of user-provided templates, a fragment library, can be searched for replacement of the original (possibly deformed) template for optimal substituent attachment positions and exit vectors.
Our eternal (academic) example of dihydrofolate reductase will provide the protein and methotrexate will be the ligand of which we consider the central phenyl ring as the template to be replaced.

Soft Subset Minimization

Preparing a Substituent-Exit-Geometry Entry (Pharmacophore)

The exit geometry of each substituent is given by its point of attachment and the exit vector of the bond to the first substituent atom. To define these quantities in Moloc, a pharmacophore entry with directed agons is well suited.
Manual pharmacophore building (old style): Automated procedure:

Template Matching

A first (old-style) version of template matching was later improved to account for selective bond types. Matching proceeds as follows:

Examination of Resuts