© The Thomson Corporation ISSN 1367-6733
Rediscovering the role of natural products in drug discovery
Manoj C Desai & Samuel Chackalamannil
There has been a steady decline in the number of new drug approvals over the past decade and the number of drugs reaching the market in 2008 is predicted to be at an all-time low . In the past, several reasons have been proposed to explain this reduction in new drug launches, such as the increasing complexity of disease targets, a higher entry standard for new drugs because they have to compete against an already improved standard of care, and increasing regulatory hurdles . While these explanations are accurate, the declining role of natural products in drug discovery research is another major factor.
Natural products have contributed significantly to the discovery of new drugs for many decades. An analysis of all small-molecule drugs that were launched worldwide during the 25-year period between 1981 and 2006 revealed that 63% of these drugs were derived from natural products . Despite this enormous impact, most major pharmaceutical companies have abandoned their research into natural products. One might ask what the reason is behind this transition.
One of the biggest challenges in drug discovery is the initial identification of a suitable lead structure that can be optimized for clinical development. The extent to which the quality of the lead dictates the success of lead optimization has only been appreciated recently. Studies of existing drugs have demonstrated that the structural and physicochemical properties of final drugs are very similar to those of the initial leads from which they were generated . Natural products have traditionally provided lead compounds for drug discovery. Since the discovery of steroids and penicillin in the first half of the 20th century, the isolation and screening of natural products, which are often guided by the lore of 'ethanocopia', such as Chinese medicine and Ayurveda, were the norm of the pharmaceutical industry. For years, the pharmaceutical industry and governments channeled substantial resources into the isolation, screening and synthesis of biologically active natural products; however, since the early 1990s, the interest in natural product chemistry has waned.
There were many reasons for this decline of natural product research in the pharmaceutical industry. The most important reason was the introduction of high-throughput screening in the late 1980s and the inability of natural products to meet the ensuing compound requirements. In addition to the inherent difficulty of collecting natural product sources and extracting their active components, the natural product extracts were often incompatible with the high-throughput screening format. Repeated hits of a natural product that had already been isolated from a different source often resulted in the duplication of efforts. Also, very often, only extremely small quantities of pure compounds were available from natural sources, and some of these natural products had highly complex structures that made total synthesis
and scale-up difficult. Occasionally, companies faced intellectual property rights involving indigenous populations that were difficult to deal with . These difficulties associated with natural products propelled research into alternative high-throughput synthetic approaches, such as combinatorial chemistry.
In this context, the combinatorial chemistry approach seemed to be a viable alternative to natural products for the generation of a large number of compounds as it has the power to synthesize a wide array of compound libraries from given intermediates; however, the early combinatorial chemistry collections were designed based on synthetic feasibility, with little regard for the drug-like nature of the targets. Lead structures were selected based on their affinity, and these leads often lacked desirable physicochemical and ADMET (adsorption, distribution, metabolism, excretion and toxicity) properties. This placed the bar for lead optimization too high, that is, the need to simultaneously optimize biological, physicochemical and ADMET properties, and this led to high attrition rates. The combinatorial libraries were often supplemented with compound collections that were acquired from non-pharmaceutical client services, but these also lacked desirable physicochemical and ADMET properties. Because there is a 10- to 14-year period between lead identification and new drug introduction, the paucity of current market launches can be traced back to the rapid transition of drug discovery research from natural products to combinatorial chemistry, and the subsequent failure of early combinatorial
chemistry to fulfill its goal. Reflecting on the failure of combinatorial chemistry, a veteran industry leader stated that the industry should (in future) try to validate new technologies "before they are extensively embraced" .
However, combinatorial chemistry has matured over the years and has found its place in the armamentarium of drug hunters. Medicinal chemists have come to appreciate the context in which combinatorial chemistry is useful and its associated limitations. Failures in lead optimization and clinical trials prompted several critical assessments of the quality of compound collections in various pharma companies, and steps have been taken to remedy these problems . Today, more drug-like compound libraries are designed and synthesized using adapted combinatorial chemistry technologies. Some of these compounds are based on natural product scaffolds. This approach is likely to yield improved returns in future drug discovery efforts.
作者:admin@医学,生命科学 2011-09-19 05:14