Designing active template molecules by combining computational de novo design and human chemist's expertise.
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, one or two aromatic rings, and a small number of rotatable bonds. In this way, we obtained a collection of scaffold- or templatelike 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 eight 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 leadlike solutions helped the medicinal chemists to select good starting points for future lead optimization, away from existing compound libraries.
Lameijer
Eric-Wubbo
EW
Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Leiden University, Post Office Box 9502, 2300RA Leiden, The Netherlands.
Tromp
Reynier A
RA
Spanjersberg
Ronald F
RF
Brussee
Johannes
J
Ijzerman
Adriaan P
AP
D000465:Algorithms; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D016208:Databases, Factual; D015195:Drug Design; D005240:Feasibility Studies; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects; D008958:Models, Molecular; D004364:Pharmaceutical Preparations / Q000138:chemical synthesis / Q000737:chemistry*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D012984:Software; D013329:Structure-Activity Relationship
D000814:Aniline Compounds; D002352:Carrier Proteins; D005663:Furans; D007473:Ion Channels; D004364:Pharmaceutical Preparations; D010880:Piperidines; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D010727:Phosphoric Diester Hydrolases; D000254:Sodium-Potassium-Exchanging ATPase