Data processing: measuring – calibrating – or testing – Measurement system in a specific environment – Biological or biochemical
Reexamination Certificate
1995-03-31
2002-01-22
Brusca, John S. (Department: 1631)
Data processing: measuring, calibrating, or testing
Measurement system in a specific environment
Biological or biochemical
Reexamination Certificate
active
06341256
ABSTRACT:
This specification includes a microfiche appendix containing a listing of the computer programs of this invention, this appendix comprising 2 microfiche of 101 total frames.
A portion of the disclosure of this patent document contains material which is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by any one of the patent disclosure, as it appears in the Patent and Trademark Office patent files and records, but otherwise reserves all copyright rights whatsoever.
1. FIELD OF THE INVENTION
The field of this invention is computer assisted methods of drug design. More particularly the field of this invention is computer implemented smart Monte Carlo methods which utilize NMR and binders to a target of interest as inputs to determine highly accurate molecular structures that must be possessed by a drug in order to achieve an effect of interest. Illustrative U.S. Patents are U.S. Pat. No. 5,331,573 to Balaji et al., U.S. Pat. No. 5,307,287 to Cramer, III et al., U.S. Pat. No. 5,241,470 to Lee at al., and U.S. Pat. No. 5,265,030 to Skolnick et al.
2. BACKGROUND
Protein interactions have recently emerged as a fundamental target for pharmacological intervention. For example, the top two major uncured diseases in the United States are atherosclerosis (the principal cause of heart attack and stroke) and cancer. These diseases are responsible for greater than 50% of all U.S. mortality and cost the U.S. economy over $200 billion per year. A consistent picture of these diseases, which has gradually emerged during the past ten years of molecular biological and medical research, views both as triggered by disordering of specific molecular recognition events that take place among sets of proteins present in both the normal and disease states.
Hierarchical, organized patterns of protein-protein interactions are often referred to as “pathways” or “cascades.” At the molecular level, cancers have been determined to be the deregulation of pathways of interacting proteins responsible for guiding cellular growth and differentiation. During the past year, individual cellular events have been organized into nearly complete mechanistic explanations of how a cell's behavior is controlled by its environment and how communication pathway errors lead to uncontrolled proliferation and cancer. Disruption in similar pathways are responsible for the proliferation of blood vessel walls marking the atherosclerotic disease state (Cook et al., 1994, Nature 369:361-362; Hall, 1994, Science 264:1413-1414; Ross, 1993, Nature 362:801-809; Zhang et al., 1993, Nature 364:308-313).
Inhibition or stimulation of particular protein-substrate interactions have long been known drug targets. Many important anti-hypertensives, neurotransmitter analogues, antibiotics, and chemotherapeutic agents act in this fashion. Captopril, an antihypertensive drug, was designed based on its ability to antagonize a focal blood-pressure-regulating enzyme.
Proteins involved in biological processes, either as part of protein-protein pathways or as enzymes, are composed of domains (Campbell et al., 1994, Trend. BioTech. 12:168-172; Rothberg et al., 1992, J. Mol. Biol. 227:367-370). Domains, or regions of the protein of stable three dimensional (secondary and tertiary) structures, play several major roles, including providing on their surface small regions (“examples of targets”), where proteins and substrates are able to bind and interact, and functioning as structural units holding other domains together as part of a large protein (tertiary and quaternary structure). The interaction surface of a domain or target is fundamental to determining binding specificity. Targets are often small enough that the principal contribution to the binding energy is short range, highly localized to several amino acids (Wells, 1994, Curr. Op. Cell Biol. 6:163-174). The functional specificity of targets and domains, responsible for the incredible diversity of cellular function, ultimately rests with the arrangement of amino acid side chains forming their interaction surfaces, or targets (Marengere et al., 1994, Nature 369:502-505).
It can be appreciated, therefore, that pharmacological intervention affecting the specific protein-protein and protein-substrate recognition events occurring at protein targets is of fundamental importance, particularly for effective drug design.
However, achieving desired pharmacological interventions in a predictable manner remains as elusive as ever. Early approaches to drug design depended on the chance observation of biological effects of a known compound or the screening of large numbers of exotic compounds, usually derived from natural sources, for any biological effects. The nature of the actual protein target was usually unknown.
2.1. TARGET STRUCTURE-BASED APPROACHES TO DRUG DESIGN
Rational approaches to drug design have met with only limited success. Current rational approaches are based on first determining the entire structure of the proteins involved in particular interactions, examining this structure for the possible targets, and then predicting possible drug molecules likely to bind to the possible target. Thus the location of each of the thousands of atoms in a protein must be accurately determined before drug design can begin. Direct experimental and indirect computational methods for protein structure determination are in current use. However, none of these methods appears to be sufficiently accurate for drug design purposes according to current rational approaches.
The primary direct experimental methods for determining the structure of proteins involved in particular interactions are X-ray crystallography, relying on the interaction of electron clouds with X-rays, and liquid nuclear magnetic resonance (NMR), relying on correlations between polarized nuclear spins interacting via indirect dipole-dipole interactions. X-ray methods provide information on the location of every heavy atom in a crystal of interest accurate to 0.5-2.0 Å (1 Å=10
−8
cm). Drawbacks of x-ray methods include difficulties in obtaining high-quality crystals, expense and time associated with the crystallization process, and difficulties in resolving whether or not the structure of the crystalline forms is representative of the in vivo conformation (Clore et al., 1991, J. Mol. Biol. 221:47; Shaanan et al., 1992, Science 227:961-964). High resolution, multidimensional, liquid phase NMR techniques represent an attractive alternative, to the extent that they can be applied in situ (i.e., in aqueous environment) to the study of small protein domains (Yu et al., 1994, Cell 76:933-945). However, the complexity of the analysis of the various mutual correlations is time consuming, and the correlations (primarily from the nuclear Overhausser effect) provide no better accuracy than X-ray methods. Isotopic enrichment of proteins with
13
C and
15
N reduces the time associated with analysis, but at a great expense (Anglister et al., 1993, Frontiers of NMR in Biology III LZ011).
Protein structures determined by any of these current methods do not predict success in subsequent drug design. Resolution obtainable either by measurement or computation, generally 0.5-2 Å, has often been found to be inadequate for effective direct drug design, or for selection of a lead compound from organic compound libraries. The resolution required to understand both drug affinity and drug specificity, although not precisely known, is probably measured in fractions of an Å, down to 0.1 Å (MacArthur et al., 1994, Trend. BioTech. 12:149-153). This accuracy appears to be beyond the capabilities of many current methodologies.
Prior research has identified tools which, although promising, cannot be used in a coordinated manner for drug design. One promising measurement approach with speed, simplicity, accuracy, and the ability to carefully control the measurement environment is rotational echo double resonance (REDOR) NMR, a type of solid state NMR (Guillion and Schaefer, 1989, J. Mag
Deem Michael W.
Rothberg Jonathan Marc
Went Gregory T.
Brusca John S.
CuraGen Corporation
Pennie & Edmonds LLP
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