A novel in silico approach to drug discovery via computational intelligence.
A computational intelligence drug discovery platform is introduced as an innovative technology designed to accelerate high-throughput drug screening for generalized protein-targeted drug discovery. This technology results in collections of novel small molecule compounds that bind to protein targets as well as details on predicted binding modes and molecular interactions. The approach was tested on dihydrofolate reductase (DHFR) for novel antimalarial drug discovery; however, the methods developed can be applied broadly in early stage drug discovery and development. For this purpose, an initial fragment library was defined, and an automated fragment assembly algorithm was generated. These were combined with a computational intelligence screening tool for prescreening of compounds relative to DHFR inhibition. The entire method was assayed relative to spaces of known DHFR inhibitors and with chemical feasibility in mind, leading to experimental validation in future studies.
Hecht
David
D
Southwestern College, 900 Otay Lakes Road, Chula Vista, California 91910, USA. dhecht@swccd.edu
Fogel
Gary B
GB
D000465:Algorithms; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001185:Artificial Intelligence; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D016571:Neural Networks, Computer; D004364:Pharmaceutical Preparations / Q000737:chemistry; D002727:Proguanil / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D012044:Regression Analysis; D015203:Reproducibility of Results; D054852:Small Molecule Libraries; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology
D000962:Antimalarials; D005493:Folic Acid Antagonists; D004364:Pharmaceutical Preparations; D054852:Small Molecule Libraries; D014227:Triazines; C026009:cycloguanil; D013762:Tetrahydrofolate Dehydrogenase; D002727:Proguanil