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Structure-based drug design has become an indispensible tool in drug discovery. The emergence of structure-based design is due to gains in structural biology that have provided exponential growth in the number of protein crystal structures, new computational algorithms and approaches for modeling protein-ligand interactions, and the tremendous growth of raw computer power in the last 30 years. Computer modeling and simulation have made major contributions to the discovery of many groundbreaking drugs in recent years. Examples are presented that highlight the evolution of computational structure-based design methodology, and the impact of that methodology on drug discovery.

Abstract:The Hebrew expression [inline-graphic 02] (“with an uplifted hand”) is used in the Hebrew Bible and the Dead Sea Scrolls to convey defiance and arrogance. It is also used to qualify intent with respect to sin. This essay examines how data from the Qumran library significantly enhance our knowledge about how the expression was used in ancient Judaism. Special emphasis is placed on how a rare meaning found in the book of Numbers was used to shape religious law in many of the sectarian texts found at Qumran. Essene writers would not have made distinctions between what modern scholars label as Priestly and Holiness source materials in pentateuchal books, but modern literary analysis of the Pentateuch can shed light on how and why certain texts had the particular influences that they did in history. This paper suggests that the legal/literary innovations of the post-exilic Holiness School ultimately played a role in the later development of Essene/ sectarian constructions of Jewish identity. Literary and linguistic analyses can provide a partial genealogy of sin between the Holiness School and the Essenes. The Holiness School’s extension of the concept of holiness from the collective to the individual made it possible for the Essenes to develop a unique notion of Jewish identity that tied the Torah faithfulness of various types of individuals to their community status.

A series of functionalized styrenic polymers were synthesized that were designed to release a low molar mass compound, a color photographic developer (a substituted phenylenediamine), when heated. The developer moieties were covalently bound via special protecting groups (“switches”) that were stable at ambient temperature but decomposed to release the developer above 100 °C. In one series, the protecting group consisted of benzylic carbamates, designed to release via a cationic mechanism. In a second series, the protecting groups comprised ethylene linkages set up for 1,2-elimination, and release occurred via an anionic mechanism. Waterborne formulations of the title polymers suitable for coating were prepared via milling, evaporative dispersion, or emulsion polymerization. The polymers were incorporated into silver halide-based photothermographic media, which were capable of forming color images after appropriate exposure and heat treatment, indicating successful controlled release of the developer. This system may be applicable to other controlled-release applications in which a bound compound is to be released when the material is heated.

β-Secretase, aka β-APP cleaving enzyme (BACE), is an aspartyl protease that has been implicated as a key target in the pathogenesis of Alzheimer's disease (AD). The identification of the protonation states of the key aspartates in β-secretase is of great interest both in understanding the reaction mechanism and in guiding the design of drugs against AD. However, the resolutions of currently available crystal structures for BACE are not sufficient to determine the hydrogen atom locations. We have assigned the protonation states of the key aspartates using a novel method, QM/MM X-ray refinement. In our approach, an energy function is introduced to the refinement where the atoms in the active site are modeled by quantum mechanics (QM) and the other atoms are represented by molecular mechanics (MM). The gradients derived from the QM/MM energy function are combined with those from the X-ray target to refine the crystal structure of a complex containing BACE and an inhibitor. A total number of 8 protonation configurations of the aspartyl dyad were considered, and QM/MM X-ray refinements were performed for all of them. The relative stability of the refined structures was scored by constructing the thermodynamic cycle using the energetics calculated by fully quantum mechanical self-consistent reaction field (QM/SCRF) calculations. While all 8 refined structures fit the observed electron density about equally well, we find the monoprotonated configurations to be strongly favored energetically, especially the configuration with the inner oxygen of Asp32 protonated and the hydroxyl of the inhibitor pointing toward Asp228. It was also found that these results depend on the constraints imposed by the X-ray data. We suggest that one of the strengths of this approach is that the resulting structures are a consensus of theoretical and experimental data and remark on the significance of our results in structure based drug design and mechanistic studies.

We have developed a new method for assigning a drug-like score to reagents. This algorithm uses topological torsion (TT) 2D descriptors to compute the subsimilarity of any given reagent to a substructural element of any compound in the CMC. The utility of this approach is demonstrated by scoring a test set of reagents derived from the “Comprehensive Survey of Combinatorial Library Synthesis:  2000” (J. Comb. Chem.). R-groups were extracted from the most-active compounds found in each of the reviewed libraries, and the distribution of the subsimilarity scores for these monomers were compared to the ACD. This comparison showed a dramatic shift in the distribution of the JCC R-group subset toward higher subsimilarity scores in comparison to the entire ACD database. The ACD was also used to examine the relationship between molecular weight and various subsimilarity scoring algorithms. This analysis was used to derive a subsimilarity score that is less biased by molecular weight.

2D fragment-based similarity searching is one of the most popular techniques for searching a large database of chemical structures and has been widely applied in drug discovery. However, its performance, especially its effectiveness in retrieving active structural analogues, has not been adequately studied. We report a series of computational experiments, where we systematically studied the influence of structural descriptors and similarity coefficients on the effectiveness of similarity searching. The study was conducted using two public large data sets, NCI anti-AIDS and MDDR. Four sets of 2D linear fragment descriptors, based on the original definitions of atom pairs and atom sequences, were compared. The effect of using the Tanimoto coefficient and the Euclidean distance was studied as a function of descriptor set. The results clearly indicate that the Tanimoto coefficient is superior to the Euclidean distance in 2D-fragment based similarity searching, in terms of hit rate, while atom sequences demonstrate the best overall performance among the structural descriptors we studied.

Scaling is a difficult issue for any analysis of chemical properties or molecular topology when disparate descriptors are involved. To compare properties across different data sets, a common scale must be defined. Using several publicly available databases (ACD, CMC, MDDR, and NCI) as a basis, we propose to define chemically meaningful scales for a number of molecular properties and topology descriptors. These chemically derived scaling functions have several advantages. First, it is possible to define chemically relevant scales, greatly simplifying similarity and diversity analyses across data sets. Second, this approach provides a convenient method for setting descriptor boundaries that define chemically reasonable topology spaces. For example, descriptors can be scaled so that compounds with little potential for biological activity, bioavailability, or other drug-like characteristics are easily identified as outliers. We have compiled scaling values for 314 molecular descriptors. In addition the 10th and 90th percentile values for each descriptor have been calculated for use in outlier filtering.

It is often impractical to synthesize and test all compounds in a large exhaustive chemical library. Herein, we discuss rational approaches to selecting representative subsets of virtual libraries that help direct experimental synthetic efforts for diverse library design. We compare the performance of two stochastic sampling algorithms, Simulating Annealing Guided Evaluation (SAGE; Zheng, W.; Cho, S. J.; Waller, C. L.; Tropsha, A. J. Chem. Inf. Comput. Sci.1999, 39, 738−746.) and Stochastic Cluster Analysis (SCA; Reynolds, C. H.; Druker, R.; Pfahler, L. B. Lead Discovery Using Stochastic Cluster Analysis (SCA):  A New Method for Clustering Structurally Similar Compounds J. Chem. Inf. Comput. Sci.1998, 38, 305−312.) for their ability to select both diverse and representative subsets of the entire chemical library space. The SAGE and SCA algorithms were compared using u- and s-optimal metrics as an independent assessment of diversity and coverage. This comparison showed that both algorithms were capable of generating sublibraries in descriptor space that are diverse and give reasonable coverage (i.e. are representative) of the original full library. Tests were carried out using simulated two-dimensional data sets and a 27 000 compound proprietary structural library as represented by computed Molconn-Z descriptors. One of the key observations from this work is that the algorithmically simple SCA method is capable of selecting subsets that are comparable to the more computationally intensive SAGE method.

The megalithic tomb of Pedra Branca lies at Montum, on the west coast of Portugal about 140 kilometers south of Lisbon by road (fig. 1). The tomb is the first in Portugal to have yielded Beaker graves overlying earlier burials; prior to its discovery, no Beaker remains had ever been noted further south than Palmela, in the estuary of the Sado river, approximately 40 kilometers from Lisbon. The tomb is situated on the top of a small hillock 100 m above sea level, separated from the Atlantic Ocean by a fertile undulating plain about 5 km in width. The Lake of Melides lies to the north and, to the east, the hills of Grandola rise steeply to an altitude of 300 m; an expanse of rough terrain stretches to the south, ravined by various small streams which flow into the Lake of Santo André on the coast.When the tomb was discovered by surveyors of the Geological Services of Portugal, it was already very badly damaged; all the orthostats had been broken for use in local construction and part of the circular covering mound had already been ploughed under. The Services therefore, decided that a salvage campaign was called for, and a team made up of the authors, was invited to carry it out with funds granted by the Calouste Gulbenkian Foundation.