iLOGP: A Simple, Robust, and Efficient Description of n-Octanol/Water Partition Coefficient for Drug Design Using the GB/SA Approach

Abstract

The n-octanol/water partition coefficient (log Po/w) is a key physicochemical parameter for drug discovery, design, and development. Here, we present a physics-based approach that shows a strong linear correlation between the computed solvation free energy in implicit solvents and the experimental log Po/w on a cleansed data set of more than 17,500 molecules. After internal validation by five-fold cross-validation and data randomization, the predictive power of the most interesting multiple linear model, based on two GB/SA parameters solely, was tested on two different external sets of molecules. On the Martel druglike test set, the predictive power of the best model (N = 706, r = 0.64, MAE = 1.18, and RMSE = 1.40) is similar to six well-established empirical methods. On the 17-drug test set, our model outperformed all compared empirical methodologies (N = 17, r = 0.94, MAE = 0.38, and RMSE = 0.52). The physical basis of our original GB/SA approach together with its predictive capacity, computational efficiency (1 to 2 s per molecule), and tridimensional molecular graphics capability lay the foundations for a promising predictor, the implicit log P method (iLOGP), to complement the portfolio of drug design tools developed and provided by the SIB Swiss Institute of Bioinformatics.

SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules

“…XLOGP3, an atomistic method including corrective factors and knowledge-based library29; WLOGP, our own implementation of a purely atomistic method based on the fragmental system of Wildman and Crippen30; MLOGP, an archetype of topological method relying on a linear relationship with 13 molecular descriptors implemented from refs 31 and 32; SILICOS-IT, an hybrid method relying on 27 fragments and 7 topological descriptors (http://silicos-it.be.s3-website-eu-west-1.amazonaws.com/software/filter-it/1.0.2/filter-it.html, accessed June 2016); and finally iLOGP, our in-house physics-based method relying on free energies of solvation in n -octanol and water calculated by the Generalized-Born and solvent accessible surface area (GB/SA) model. iLOGP was benchmarked on two drug or drug-like external sets and performed equally as or better than six well-established predictors16. The consensus log P o/w is the arithmetic mean of the values predicted by the five proposed methods.…”

“…pk-CSM14 and admetSAR15) and apart from unique access to proficient methods (e.g. iLOGP16 or the BOILED-Egg17), SwissADME strong points are, non-exhaustively: different input methods, computation for multiple molecules, and the possibility to display, save and share results per individual molecule or through global intuitive and interactive graphs. Finally, SwissADME is integrated in the SwissDrugDesign workspace.…”

Computational prediction of octanol–water partition coefficient based on the extended solvent-contact model

“…However, the accuracy seems to be insufficient when compared to the recently reported methods such as QSPR modeling with intramolecular interaction parameters [13] and the hybrid GB/SA model [15]. To address the dependence of the LogP prediction results on the contents of the training and test sets, we repeated the optimization of the atomic solvation parameters and the calculation of molecular LogP values using the two additional training/test set combinations.…”

“…Very recently, Daina et al. developed a rigorous method for predicting LogP by combining the generalized Born and solvent accessible surface area models [15], which was referred to as iLogP method. Besides the high accuracy in estimating the molecular LogP values, iLogP method was also found to be adequate for coping with a large number of molecules in reasonably short time frame despite the requirement for computing various molecular descriptors.…”

Antifungal Activity of a Secondary Metabolite of Azadirachta Indica and Its Derivatives – An in Silico Study

“…The protein and ligand were docked with iGEMDOCK and Autodock Vina [24], the results were retrieved on the basis of energy values, Van der Waals force, binding affinity between protein and ligand. The SAR molecules were generated with the help of SWISS ADME [25][26][27] online tool. In a study by Jeyam et al showed that a good interaction between 1,3 β glucan synthase with 20 phytoconstituents and the inhibition of 1,3 β glucan synthase was better than echinocandins [28].…”