Advanced Scaffold Hopping and beyond

The final result of many computational tools and methods used in drug discovery is a mathematical model or a 3D graphic. However, drug design aims to obtain real compounds, synthetically affordable. SHOP was developed around this central concept, as a tool able to provide solutions to diverse practical problems in terms of a list of synthetically accessible derivatives.

SHOP can deal with two kinds of problems:

I have a suitable compound, but I cannot use it

This is a rather common situation. We have identified a suitable lead compound, but it cannot be used due to chemical problems, ill DMPK properties or IP conflicts. In these cases, SHOP allows to replace a large part of the structure (the scaffold) keeping in place critically important substituents. The program SHOP can perform a search for a bioisosteric replacement on a database of fragments (standards or built ad hoc for this series) and yields a result a list of suitable candidates. The situation is illustrated in the figure: the original fragment is converted to an array of descriptors (based on molecular interaction fields, atoms distances etc.) and the fragment database is searched to obtain similar fragments. The closest fragments were then used to rebuild the original compound and a ranked list of candidates is presented.

I have the structure of my target receptor complexed with a ligand, but I don’t know how to exploit this information

Obtaining the structure of a ligand-receptor complex is not the end of our research. This valuable information must be exploited to obtain alternative compounds which can also bind with high affinity to the same binding pocket. Please notice that in this case we are not constrained to search fragments similar to the original scaffold but fragments complementary to the receptor. The procedure used by SHOP is illustrated in the next figure and, as in the previous case, the result is a list of synthetically accesible derivatives.

In this case, the program search fragments with physoco-chemical properties which are complementary to those obtained in the ligand binding pocket. In addition, SHOP actually docks the fragments within the binding site and rejects all those unable to fit into the pocket. As a bonus, the program is able to analyze the receptor interaction and present a comparative, per residue, analysis of the ligand-receptor energies with both the original and the novel compound.

SHOP is not virtual screening

Virtual screening methods provide as a result structures which are completely different from the original template. SHOP only replaces a part of the original molecule. In many cases this is a large advantage. Why replacing all the original structure when we know that it works! With SHOP, you can change only the part that prevents the use of the original template due to DMPK, IP or chemical derivability problems.

An advanced GUI

SHOP was built for the synthetic chemist. The client contains an extremely simple graphic interface which allow to access to all the program functionalities with a few mouse clicks. If you are used to draw your molecules in 2D in your computer, you will find the use of SHOP very simple. All the operations are carried out interactively and you will obtains results in a term of minutes. The Linux and Windows versions share exactly the same graphical interface and the same ease of use. Please check our screenshots or contact Lead Molecular for further information about the software capabilities or a free demo version.

Features and benefits

  • Unique tool for bioisosteric fragment replacement
  • Template based or receptor based, using state-of-the-art molecular descriptors
  • Use of extremely large databases of fragments
  • Easily customizable databases to guarantee synthetically feasible compounds
  • Easily integrable DMPK prediction tools
  • User friendly graphical environment designed for the synthetic chemist
  • Linux and Windows versions

Technical specifications

The SHOP software consist on two separate components: a server and a thin client. In the simplest configuration both component can run on a single computer. Corporate installations can have the server installed in a powerful central server receiving request from many clients.

SHOP runs in Windows or Linux environments (both servers and clients). The computational requirements of the thin client are very modest and it can run efficiently even in cheap or old windows boxes.


We have collected a set of screenshoots which can give you an idea of the application “look and feel”.



  • Bergmann R, Linusson A, Zamora I. SHOP: scaffold HOPping by GRID-based similarity searches. J Med Chem. 2007 50(11):2708-17.
  • Ahlström MM, Ridderström M, Luthman K, Zamora I. Virtual screening and scaffold hopping based on GRID molecular interaction fields. J Chem Inf Model. 2005 45(5):1313-23.

SHOP is a project funded by Lead Molecular Design and developed at the PhI-GRID. Academic and commercial licenses can be obtained from Molecular Discovery Ltd.