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Patients with reported mild asthma who demonstrated significant decrease in forced expiratory volume in 1 second ([FEV.sub.1]) following exercise were treated with montelukast, a leukotriene-receptor antagonist, or placebo for 12 [...]

The recently described molecular mechanics Poisson−Boltzmann surface area (MM-PBSA) method for calculating free energies is applied to a congeneric series of 16 ligands to p38 MAP kinase whose binding constants span approximately 2 orders of magnitude. These compounds have previously been used to test and compare other free energy calculation methods, including thermodynamic integration (TI), OWFEG, ChemScore, PLPScore, and Dock Energy Score. We find that the MM-PBSA performs relatively poorly for this set of ligands, yielding results much inferior to those from TI or OWFEG, inferior to Dock Energy Score, and not appreciably better than ChemScore or PLPScore but at an appreciably larger computational cost than any of these other methods. This suggests that one should be selective in applying the MM-PBSA method and that for systems that are amenable to other free energy approaches, these other approaches may be preferred. We also examine the single simulation approximation for MM-PBSA, whereby the required ligand and protein trajectories are extracted from a single MD simulation rather than two separate MD runs. This assumption, sometimes used to speed the MM-PBSA calculation, is found to yield significantly inferior results with only a moderate net percentage reduction in total simulation time.

Precise thermodynamic integration free energy simulations have been applied to a congeneric series of 16 inhibitors to the p38 MAP kinase protein for which the experimental binding data (IC50) is known. The relative free energy of binding for each compound has been determined. For comparison, the same series of compounds have also scored using the best rapid scoring functions used in database screening. From the results of these calculations, we find (1) that precise free energy simulations allow predictions that are reliable and in good agreement with experiment; (2) that predictions of lower reliability, but still in good qualitative agreement with experiment, can be obtained using the OWFEG free energy grid method, at a much lower computational cost; (3) and that other methods, not based on free energy simulations yield results in much poorer agreement with experiment. A new predictive index, which measures the reliability of a prediction method in the context of normal use, is defined and calculated for each scoring method. Predictive indices of 0.84, 0.56, 0.04, −0.05, and 0.25 are calculated for thermodynamic integration, OWFEG, ChemScore, PLPScore, and Dock Energy Score, respectively, where +1.0 is perfect correct prediction, −1.0 is perfect incorrect prediction, and 0.0 is random.

A new approach to rapidly score protein−ligand interactions is tested on several protein−ligand systems. Results using this approach − the OWFEG free energy grid − are quite promising and are generally in better agreement with experiment (in some cases much better) than those obtained employing scoring techniques currently in wide use. The OWFEG free energy grid is generated from a one-window free energy perturbation MD simulation (Pearlman, D. A. J. Med. Chem. 1999, 42, 4313−4324). The OWFEG approach is applied to three protein systems:  IMPDH, MAP kinase p38, and HIV-1 aspartyl protease. OWFEG scores are compared to experimental Ki and IC50 data in each case. Empirical scoring functions applied to the same systems for comparison include ChemScore, Piecewise Linear Potential (PLP), and Dock energy score.

Traditional window-based free energy calculations can precisely determine the free energy corresponding to a molecular change of interest. However, calculations performed in this fashion are typically slow and resource-intensive, which renders them less than ideal for drug design. To circumvent this drawback, a new approximate free energy method, OWFEG, has been developed and tested. OWFEG replaces the exact free energy calculation for a single change with a set of approximate calculations for a grid of possible changes surrounding a molecule. One of the key features of OWFEG is that a floating independent reference frame (FIRF) is used, so that each grid point moves with the region of the molecule to which it is closest. In this way, this approach has been made applicable to flexible molecules. OWFEG is applied to two model systems and then to the FKBP-12·FK506 protein−ligand complex. On the basis of the results of these tests, this approximate method shows promise as a predictive tool for drug design.