4SCan/vADME: intelligent library screening as a shortcut from hits to lead compounds.
Managing to solve the first step in drug discovery - the hit finding - can be a quite elaborate task, but it is only the initial step to the final goal; hit-to-lead optimisation still lies ahead and consumes even more time and resources. The solution is rather simple, that is, to take only the most promising compounds into account; but who is going to decide which ones are the most promising among a list of tens of millions of compounds in a virtual combinatorial library? 4SCan/vADME helps by bridging the gap between virtual (combinatorial) libraries designed by chemists and the in silico methods, docking and alignment, for screening databases. After choosing a random starting set, the implemented learning and prediction algorithm iteratively considers only combinations of fragments that have shown to result in more suitable interactions by the chosen method. ADME properties of the final list are then calculated via several in silico methods, resulting in a combined evaluation of the individual compound's target-specific, as well as ADME, properties. Based on the latter list of evaluated compounds, medicinal chemists can then decide which compounds might be the best ones to synthesise first and to serve as possible lead candidates. Following a brief introduction to virtual high-throughput screening techniques, the 4SCan/vADME method is outlined and discussed in this paper, using an example coming out of the 4SC pipeline.
Herz
Thomas
T
4SC AG, Chem & Bioinformatics, Am Klopferspitz 19a, D-82152 Martinsried, Germany. thomas.herz@4sc.com
Wolf
Kristina
K
Kraus
Juergen
J
Kramer
Bernd
B
D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D003460:Crystallization; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism; D016208:Databases, Factual; D000090722:Dihydroorotate Dehydrogenase; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007408:Intestinal Absorption; D008024:Ligands; D008954:Models, Biological; D008958:Models, Molecular; D015394:Molecular Structure; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors / Q000737:chemistry; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D012995:Solubility; D014584:User-Computer Interface
D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D008024:Ligands; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D044925:Oxidoreductases Acting on CH-CH Group Donors