Structure Based Drug Design Examples

4.04.2.1 Hemoglobin The First Drug Design Target Perutz and colleagues, starting with the first low-resolution structures in the late 1950s, took 25 years to solve the highresolution structures of oxy and deoxy horse (1968, 1970) and human Hb (19 83, 19 84).70-73 Perutz and co-workers subsequently determined the structures of a number of mutant Hb that caused different medical maladies.74-86 The solved structures readily explained at the molecular level the reason for the physical impairments...

The GRID Force Field

MIFs describe the spatial variation of the probe-target interaction energy and provide information on the favorable and unfavorable sites for a certain probe around a given target. The energy function Exyz at each xyz grid position is the sum of many different terms The term Elj is the Lennard-Jones potential, whereas Eel is the electrostatic contribution, and Ehb is the hydrogen bond potential each individual term is the sum of all the interactions between the probe and each atom of the...

References

Graph. Model. 2002, 20, 269-276. 2. Shen, M. Beguin, C. Golbraikh, A. Stables, J. P Kohn, H. Tropsha, A. J. Med. Chem. 2004, 47, 2356-2364. 3. Hansch, C. Muir, R. Fujita, T Maloney, P. Geiger, E. Streich, M. J. Am. Chem. Soc. 1963, 85, 2817-2824. 4. Hammett, L. P. Chem. Rev. 1935, 17, 125-136. 5. Hansch, C. Leo, A. Exploring QSAR. In Fundamentals and Applications in Chemistry and Biology Hellen, S., Ed. American Chemical Society Washington, DC, 1995 Vol. 1,...

Physical Properties Governing Ligand Receptor Binding

As the lock-and-key model suggests, shape complementarity is very important for ligand-receptor binding and specificity. The overlap of atoms of the ligand and the receptor is prohibited by electron-electron repulsion. Clashes draw a large energetic penalty. In studies of receptor-ligand interactions, this penalty is usually modeled by the first term in the Lennard-Jones energy function8'9 The sum is over all ligand-receptor atom pairs and is a function of the distance, r, between the atoms in...

Key Quantitative Structure Activity Relationship Concepts

An inexperienced user or sometimes even an avid practitioner of QSAR could be easily confused by the diversity of methodologies and naming conventions used in QSAR studies. 2D or three-dimensional (3D) QSAR, variable selection or artificial neural network (ANN) methods, Comparative molecular field analysis (CoMFA), or binary QSAR present examples of various terms that may appear to describe totally independent approaches, which cannot be generalized or even compared to each other. In fact, any...

Applications of Comparative Models

There is a wide range of applications of protein structure models (Figure 4).1,175-180 For example, high- and medium-accuracy comparative models are frequently helpful in refining functional predictions that have been based on a sequence match alone because ligand binding is more directly determined by the structure of the binding site than by its sequence. It is often possible to predict correctly features of the target protein that do not occur in the template structure.181,182 For example,...

Structure Based Drug Design A Historical Perspective and the Future

D J Abraham, Virginia Commonwealth University, Richmond, VA, USA 2007 Elsevier Ltd. All Rights Reserved. 4.04.1.1 Paul Ehrlich and the Nature of the Receptor 66 4.04.1.2 Theory and Methods 66 4.04.1.2.1 X-ray crystallography 66 4.04.1.2.2 X-ray crystal data collection 66 4.04.1.2.3 Computing advances 67 4.04.1.2.4 Molecular models to molecular graphics to molecular modeling computer-aided 4.04.1.2.5 Nuclear magnetic resonance 69 4.04.1.2.6 Electron diffraction 69 4.04.1.2.7 Structure-based drug...

The Future

4.04.4.1 High-Throughput Crystallography Crystallography continues to undergo dramatic changes.168 New and improved methodologies are continually evolving in robotics, x-ray sources, computational power, crystal-growing screens, molecular genetics, and preparation of adequate sources of desired targets. More importantly, these improved technologies are integrated in both industrial and academic laboratories. The advent of companies specifically organized and funded to perform high-throughput...

Introduction

Drug discovery is a very complex and difficult scientific endeavor, which frequently results in extremely expensive failures. Virtually all the pharmaceutical companies have experienced the painful loss of new chemical entities NCEs in late stage preclinical or clinical development phases as well as the withdrawal of marketed products. Such late stage failures are very costly, both in terms of time and money.1 A detailed analysis indicates that roughly one-third of the projects fail to enter...

Ligand Based Methods for Combinatorial and Parallel Libraries

Most of the methods available for ligand-based combinatorial library design have been extensively reviewed.50'51 Most will be described briefly for purposes of completeness. Emphasis will be placed on newer literature and less reviewed methods. 4.14.2.1.1 Descriptor and property-based diversity methods, principal component analysis, clustering, and design of experiment The use of property descriptors was among the earliest methods applied to the creation of diverse compound libraries. Since...

Summary and Conclusions

In this chapter we have surveyed a broad range of techniques that are widely used in computational drug discovery. Some of these methods trace their origins to the earliest days of computational molecular science, and continue to present challenges to the computational chemistry community. As computer power has increased so too has the desire to study larger and more complex systems, or to apply the methods to much larger collections of compounds in virtual screening experiments. New force...

Molecular Mechanics and Empirical Force Field Methods

A key requirement in molecular modeling is to be able to calculate the energy of an arrangement of atoms and or molecules in 3D space. There exist a variety of methods that can be used to perform such calculations. The most 'fundamental' way to tackle this problem is to use quantum mechanics, wherein the Schrodinger equation is solved for the distribution of electrons and atoms in the system in order to derive a wave function from which other properties can be derived. As will be described...

Dissimilarity Based Compound Selection

DBCS methods involve selecting a subset of compounds directly based on their pairwise dissimilarities. They are iterative procedures whereby one compound is selected in each iteration. The basic algorithm for DBCS is outlined below 1. Select a compound and place it in the subset. 2. Calculate the dissimilarity between each compound remaining in the dataset and the compounds in the subset. 3. Choose the next compound as that which is most dissimilar to the compounds in the subset. 4. If there...

Acknowledgments

Financial support from the Klaus Tschira Foundation is gratefully acknowledged. 1. Fischer, E. Ber. Deutsch Chem. Ges. 1894, 27, 2985-2993. 2. Burgen, A. S. V Roberts, G. C. K. Feeny, J. Nature 1975, 253, 753-755. 3. Koshland, D. E., Jr. Proc. Natl. Acad. Sci. USA 1958, 44, 98-123. 4. J Tsai, C. Ma, B. Nussinov, R. Proc. Natl. Acad. Sci. USA 1999, 96, 9970-9972. 5. Teague, S. J. Nat. Rev. Drug Disc. 2003, 2, 527-541. 6. Schames, J. R. Henchman, R. H. Siegel, J. S. Sotriffer, C. A. Ni, H....

The active analog approach and receptor

If one has enough SAR information to propose the points to match, the problem becomes simply selecting the proposed bioactive conformation s of each compound. One approach to this problem is to perform rigid rotation of all rotatable bonds in each molecule, tabulating which distance bins between the atoms or points of interest are occupied by a conformation of reasonable energy.57-59 Proposed bioactive conformations thus correspond to conformations that occupy the distance bins occupied by all...