Drug discovery method and apparatus

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Methods and systems for drug discovery and development are disclosed. Methods and system consistent with the present invention discover drugs. One or more databases comprising chemical and biological interaction data and one or more computer-based data analysis programs may be used to identify compounds that have desired activity at two or more molecular targets that are associated with a disease state for which the drug discovery and development are directed. In addition, one or more databases comprising chemical and biological interaction data and one or more computer-based data analysis programs may be used to identify compounds that (a) have desired activity at one or more molecular targets that are associated with a disease state for which the drug discovery and development are directed and (b) do not have activity or have substantially reduced activity that is undesired at one or more molecular targets that are associated with possible side effects, toxicity, adverse ADME properties, or other properties not intended to be manifested by compounds being developed to treat the disease state associated with the drug discovery.

BACKGROUND OF THE INVENTION：The traditional paradigm for drug discovery and development has been basically a linear process. During the early stages of the drug discovery process, large compound libraries, numbering hundreds of thousands to millions of chemical compounds (synthetic, small organic molecules or natural products, for example) are screened or tested for biological activity at any one of hundreds of molecular targets in order to find potential new drugs, or lead compounds. The active compounds, or hits, from this initial screening process are then tested sequentially through a series of other in vitro and in vivo tests to further characterize the active compounds. A progressively smaller number of the presumptive "best" compounds at each stage are selected for testing at the next stage, eventually leading to one or at most a few drug candidates (for those "successful" discovery programs) being selected to proceed to Investigational New Drug (IND) status and be tested in human clinical trials. If, at any stage along the linear sequence of tests and decision points, a hit, lead compound, or drug candidate fails to meet the standards for continued development as a drug, the process of discovery and development must start over again. Unfortunately, under the traditional paradigm, the failure rate is high - more than 90% of drug candidates that reach IND status fail to gain marketing approval by the Food and Drug Administration (FDA). About one-half of these failures are due to undesirable or adverse side effects and the other half to insufficient efficacy.

The pharmaceutical industry has directed its past drug development efforts at only about 500 pharmacological targets, which are generally proteins such as receptors or enzymes associated with disease states. As a result of efforts to sequence the human genome, it now appears that there may be a total of 10,000 pharmaceutically relevant protein targets. This represents a 20-fold increase in the number of drug targets that may be addressable in the next decade. At the same time, advances in the automation of chemical synthesis, commonly known as combinatorial chemistry, have led to substantial increases in the size of chemical libraries available to the drug industry to screen against pharmacological targets for drug discovery. As a result, compound libraries at major drug companies are now some 10-fold larger that they were just three-to-five years ago, numbering well over 1,000,000 chemicals at many companies.

Although new drug discovery technologies have produced an explosion in the number of compounds emerging from the initial discovery phase, this has not translated into a proportional increase in new and safer drugs reaching the market. Genomics, combinatorial chemistry and high-throughput screening have produced more drug targets and more compounds to screen in a more rapid format, but the end result remains largely unchanged. Lead compound attrition has now become the primary problem for the industry. A majority of the small organic molecules that emerge from drug discovery with confirmed biological activity against a macromolecular drug target will fail in some subsequent stage of the development process. Often such problems do not become evident until the lead compound has reached Phase II or Phase III human clinical trials. This means that the drug development company has wasted substantial time, money and effort. There is a need to understand what causes failure in the late stages of drug development and to correct the discovery process at the early stages to minimize those late-stage failures. Drug Efficacy and Safety - There are many pharmaceutical companies, large and small, domestic and international. Yet, the primary model of current drug discovery and the infrastructure of the industry are essentially identical. Conventional approaches to drug discovery focus on chemical intervention at a single biochemical target or mechanism. Based on this concept, the aims of drug discovery and development are to find and to produce small molecules that are highly specific with respect to one specific macromolecule, with the intent of potently intervening, interrupting and modulating the biochemical or biological function of a single biological target. The hope of the pharmaceutical industry is that such potent "interruption or modulation" will produce some beneficial effects ameliorating certain conditions associated with disease progression.

In contrast to the drug discovery industry, medical practitioners take a different approach. Clinicians often resort to multiple drug cocktails for disease treatments. One of the well-know examples of multiple drug combinations is in the treatment of AIDS by employing cocktails of reverse transcriptase inhibitors and protease inhibitors. Another example is in the treatment of bacterial infections employing lactamase inhibitors (e.g., clavulanate) with cell wall synthesis inhibitors, and yet another example is in hypertension management employing ACE inhibitors along with diuretic drugs. Drug manufacturers have also adopted this approach and have developed similar products for management of many chronic diseases. For example, CombiNent, a medication for asthma, is a combination of a muscarinic (M3) antagonist and a beta adrenoceptor-blocker (beta-2); Claritin-D, an over-the-counter (OTC) allergy medication, is a combination of Loratadine (antihistamine) and pseudoephedrine. In fact, in recent years, examples of drug combinations or multi- drug regimens have become commonplace in medical practice.