Molpher-lib is based on the program Molpher which implements systematic chemical space exploration using a method called molecular morphing. Its purpose is not only to make molecular morphing easily accessible to a wider audience, but it also strives for becoming a powerful, transparent and easy-to-use de novo drug design tool.
On this simple web page, we will try to explain what molecular morphing is, how it can be used in de novo drug design and we will hint at some advanages Molpher-lib has over the original Molpher. There is also a page dedicated to some quick usage examples as well as an extensive documentation.
Molecular morphing is an atom-based de novo drug design method that uses stochastic optimization to search for a 'path' in chemical space. The so called path is a set of molecular structures that result from application of small structural modifications of the molecular structure of an input molecule. An example of such a path can be seen in the figure below.
Example of a path generated by Molpher using some basic structural modifications. The modifications are shown as codes below the arrows (RA = remove atom, RB = remove bond, BR = bond reroute, MA = mutate atom).
The original Molpher software was programmed to find a set of modifications needed to transform one molecular structure into another. Therefore, it can generate a set of 'hybrid' structures that combine the structural features of two input molecules; very much like morphing in computer graphics.
One possible application of such algorithm is sampling unknown chemical space 'around' molecules with confirmed biological activity (see figure below). Here, Molpher (or Molpher-lib) can be used to generate a focused virtual library of hybrid structures that are derived from known active molecules. Such library could, for example, be used in a virutal screening campaign that might yield new ligands with new chemotypes.
Schematic depiction of a focused chemical space exploration experiment using molecular morphing. Multiple paths are generated between every pair of known active molecules (lines connecting the big diamonds, one example path is highlighted in red). Every path consists of intermediate (hybrid) structures (morphs, shown as small diamonds) that combine structural features of the pair that they connect. It is also possible (and generally a good idea) to impose constraints on the search space that will prevent the algorithm from generating structures with undesirable properties (represented by the thick black lines enclosing the explored area).
The motivation to develop Molpher-lib was mainly driven by various shortcomings of Molpher:
These problems were eliminated in Molpher-lib as follows:
Thanks to all of the above the library has prerequisites to become a comprehensive and flexible de novo drug design framework. In the future, Molpher-lib will not only offer molecular morphing functionality, but will also include features that will allow for arbitrary evolution of molecular structures. This will be particularly useful in lead optimization and to quickly test new ideas in computer-aided drug design.