07 - 191 7 Designing Active Template Molecules by Combining...

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191 7 Designing Active Template Molecules by Combining Computational De Novo Design and Human Chemist’s Expertise Eric-Wubbo Lameijer, Reynier A. Tromp, Ronald F. Spanjersberg, Johannes Brussee, and Adriaan P. IJzerman Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands This chapter was first published in the Journal of Medicinal Chemistry, reference: Lameijer, E.W.; Tromp, R.A.; Spanjersberg, R.F.; Brussee, J.; IJzerman, A.P. Designing Active Template Molecules by Combining Computational De Novo Design and Human Chemist's Expertise. J. Med. Chem. , 2007 , 50 (8), 1925–1932. Abstract We used a new software tool for de novo design, the “Molecule Evoluator”, to generate a number of small molecules. Explicit constraints were a relatively low molecular weight and otherwise limited functionality, for example low numbers of hydrogen bond donors and acceptors, 1 or 2 aromatic rings, and a small number of rotatable bonds. In this way we obtained a collection of scaffold- or template-like molecules rather than fully “decorated” ones. We asked medicinal chemists to evaluate the suggested molecules for ease of synthesis and overall appeal, allowing them to make structural changes to the molecules for these reasons. On the basis of their recommendations we synthesized 8 molecules with an unprecedented (not patented) yet simple structure, which were subsequently tested in a screen of 83 drug targets, mostly G protein-coupled receptors. Four compounds showed affinity for biogenic amine targets (receptor, ion channel and transport protein), reflecting the training of the medicinal chemists involved. Apparently the generation of lead-like solutions helped
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192 the medicinal chemists to select good starting points for future lead optimization, away from existing compound libraries. Introduction Chemical space is vast – the number of potential drug-like molecules has been estimated to be beyond the number of atoms in the universe. 1,2 This is in sharp contrast with the total count of molecules in large compound databases such as CAS, with approximately 25 million references to chemical compounds. 3 Hence, de novo design is crucial to cover more of the chemical universe. Computational methods are particularly suitable for this goal, as they can quickly generate and store thousands of putative structures. Currently, there are dozens of de novo design programs, many of which have been covered in a recent review. 4 For example, the program CoG (Compound Generator) of Brown et al. 5 constructs molecules based on atoms and fragments that have been given as input to the program, eventually yielding molecules that resemble a number of selected ligands. Other programs construct new molecules based on the structure of the target protein. For example, DycoBlock 6 takes a list of fragments and searches for their optimal position in the active site of the protein. Then it searches for combinations of building blocks that could be linked together to form a new molecule.
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07 - 191 7 Designing Active Template Molecules by Combining...

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