PhDD: a new pharmacophore-based de novo design method of drug-like molecules combined with assessment of synthetic accessibility.
This account describes a new pharmacophore-based de novo design method of drug-like molecules (PhDD). The method PhDD first generates a set of new molecules that completely conform to the requirements of a given pharmacophore model, followed by a series of assessments to the generated molecules, including assessments of drug-likeness, bioactivity, and synthetic accessibility. PhDD is tested on three typical examples, namely, pharmacophore hypotheses of histone deacetylase (HDAC), cyclin-dependent kinase 2 (CDK2) and HIV-1 integrase (IN) inhibitors. The test results demonstrate that PhDD is able to generate molecules with novel structures but having similar biological functions with existing inhibitors. The validity of PhDD together with its ability of assessing synthetic accessibility makes it a useful tool in rational drug design.
Huang
Qi
Q
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, #1 Keyuan Road 4, Chengdu, Sichuan 610041, China.
Li
Lin-Li
LL
Yang
Sheng-Yong
SY
D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors; D016208:Databases, Factual; D015195:Drug Design; D019428:HIV Integrase Inhibitors / Q000737:chemistry; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D019428:HIV Integrase Inhibitors; D051357:Cyclin-Dependent Kinase 2