Prediction of the binding affinity of compounds with diverse scaffolds by MP-CAFEE.
Accurate methods to predict the binding affinities of compounds for target molecules are powerful tools in structure-based drug design (SBDD). A recently developed method called massively parallel computation of absolute binding free energy with a well-equilibrated system (MP-CAFEE) successfully predicted the binding affinities of compounds with relatively similar scaffolds. We investigate the applicability of MP-CAFEE for predicting the affinity of compounds having more diverse scaffolds for the target p38α, a mitogen-activated protein kinase. The calculated and experimental binding affinities correlate well, showing that MP-CAFEE can accurately rank the compounds with diverse scaffolds. We propose a method to determine the optimal number of sampling runs with respect to a predefined level of accuracy, which is established according to the stage in the SBDD process being considered. The optimal number of sampling runs for two key stages-lead identification and lead optimization-is estimated to be five and eight or more, respectively, in our model system using Cochrans sample size formula.
Medicinal Chemistry Research Laboratories II, Mitsubishi Tanabe Pharma Corporation, Toda, Saitama 335-8505, Japan. Electronic address: Okada.Okimasa@mc.mt-pharma.co.jp.
Okimasa
O
Okada
Hiroshi
H
Yamashita
Kei
K
Takedomi
Satoshi
S
Ono
Shinji
S
Sunada
Hideo
H
Kubodera
D030562:Databases, Protein; D015195:Drug Design; D048308:Mitogen-Activated Protein Kinase 14 / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012984:Software; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
D014867:Water; D048308:Mitogen-Activated Protein Kinase 14
Binding affinity prediction; Diverse scaffolds; MP-CAFEE; Molecular dynamics; Optimal sampling size; massively parallel computation of absolute binding free energy with a well-equilibrated system; p38α MAP kinase