Information theory-based scoring function for the structure-based prediction of protein-ligand binding affinity.

The development and validation of a new knowledge based scoring function (SIScoreJE) to predict binding energy between proteins and ligands is presented. SIScoreJE efficiently predicts the binding energy between a small molecule and its protein receptor. Protein-ligand atomic contact information was derived from a Non-Redundant Data set (NRD) of over 3000 X-ray crystal structures of protein-ligand complexes. This information was classified for individual "atom contact pairs" (ACP) which is used to calculate the atomic contact preferences. In addition to the two schemes generated in this study we have assessed a number of other common atom-type classification schemes. The preferences were calculated using an information theoretic relationship of joint entropy. Among 18 different atom-type classification schemes "ScoreJE Atom Type set2" (SATs2) was found to be the most suitable for our approach. To test the sensitivity of the method to the inclusion of solvent, Single-body Solvation Potentials (SSP) were also derived from the atomic contacts between the protein atom types and water molecules modeled using AQUARIUS2. Validation was carried out using an evaluation data set of 100 protein-ligand complexes with known binding energies to test the ability of the scoring functions to reproduce known binding affinities. In summary, it was found that a combined SSP/ScoreJE (SIScoreJE) performed significantly better than ScoreJE alone, and SIScoreJE and ScoreJE performed better than GOLD::GoldScore, GOLD::ChemScore, and XScore.

A phase II trial of pemetrexed in advanced breast cancer: clinical response and association with molecular target expression.

PURPOSE: This phase II trial of pemetrexed explored potential correlations between treatment outcome (antitumor activity) and molecular target expression. EXPERIMENTAL DESIGN: Chemonaïve patients with advanced breast cancer received up to three cycles of pemetrexed 500 mg/m2 (10-minute i.v. infusion) on day 1 of a 21-day cycle, with folic acid and vitamin B12 supplementation. Tumors were surgically removed after the last cycle of pemetrexed as clinically indicated. Biopsies were taken at baseline, 24 hours after infusion in cycle 1, and after cycle 3. RESULTS: Sixty-one women (median age, 46 years; range, 32-72 years) were treated and were evaluable for response. Objective response rate was 31%. Simple logistic regression suggested a potential relationship between mRNA expression of thymidylate synthase (TS) and pemetrexed response (P = 0.103). Based on threshold analysis, patients with "low" baseline TS (< or = 71) were more likely to respond to pemetrexed than patients with "high" baseline TS (>71). Expression of baseline dihydrofolate reductase and glycinamide ribonucleotide formyl transferase tended to be higher in responders but this association was not significant (P > 0.311). TS expression increased significantly between baseline and biopsy 2 (P = 0.004) and dropped to near baseline levels at biopsy 3. Conversely, dihydrofolate reductase and glycinamide ribonucleotide formyl transferase decreased after pemetrexed chemotherapy. CONCLUSIONS: Our results suggest a potential association between "low" pretreatment TS expression levels and response to pemetrexed chemotherapy. Future trials examining expression levels of other genes important to the folate pathway and/or breast cancer may identify a more robust multigene profile that can better predict response to this novel antifolate.