e-LEA3D: a computational-aided drug design web server

Abstract

e-LEA3D web server integrates three complementary tools to perform computer-aided drug design based on molecular fragments. In drug discovery projects, there is a considerable interest in identifying novel and diverse molecular scaffolds to enhance chances of success. The de novo drug design tool is used to invent new ligands to optimize a user-specified scoring function. The composite scoring function includes both structure- and ligand-based evaluations. The de novo approach is an alternative to a blind virtual screening of large compound collections. A heuristic based on a genetic algorithm rapidly finds which fragments or combination of fragments fit a QSAR model or the binding site of a protein. While the approach is ideally suited for scaffold-hopping, this module also allows a scan for possible substituents to a user-specified scaffold. The second tool offers a traditional virtual screening and filtering of an uploaded library of compounds. The third module addresses the combinatorial library design that is based on a user-drawn scaffold and reactants coming, for example, from a chemical supplier. The e-LEA3D server is available at: http://bioinfo.ipmc.cnrs.fr/lea.html.

Figure 1.

Interplay between the three e-LEA3D modules.

Figure 2.

Input and Output contents of the de novo drug design module. Inputs are the structure of the RXRα nuclear receptor and the building block ‘benzoic acid’, a substructure of the approved drug bexarotene present in the crystallized structure (residue name 9RA; the picture has been produced using PyMOL). The composite scoring function includes a docking by the program PLANTS in the RXRα binding site and a calculation of the molecular weight that must be ≤469. Outputs are: (a) the follow-up of the fittest molecule of each generation. Only the first and the last generation are presented. The score in percentage is displayed (81.56% for the best candidate) as well as its composition: the PLANTS score (–94.67) and the molecular weight (357). A second score in parenthesis, the Xscore (37), evaluates the docking pose from PLANTS (9.07). The molecular composition and the conformer number are given. The best candidate is a combination of the building block ‘benzoic acid’ (lego 0) with the lego number 758. The first building block (lego 0) is connected by its atom number 6 (coded by 1*6) with the second building block (lego 758) by its atom number 4 (2*4). (b) A click on the file name in blue displays the molecule in the java applet Jmol. The backbone of the active site is depicted in cyan and the side chains of basic residues are colored in blue. The side chain of the ARG316 is involved in an ionic bond with the carboxylate of the ligand whose carbons are colored in grey and oxygens in red. (c) The superimposition of the de novo candidate in blue on the co-crystallized drug bexarotene in green. The benzoic acid groups are perfectly superimposed.