Drug Discovery from Natural Products – A New Beginning

Nageswara Rao Thalapaneni, Mohana Lakshmi and Subhash C. Mandal

Abstract: Natural Products are very valuable pharmaceutical leads due to their potency against often difficult targets, but they can suffer from issues such as poor Pharmacokinetics, and their intractability to synthetic chemistry has hindered their use. The rapid advancement in molecular biology, such as rapid gene sequencing, has facilitated the wider application of bioengineering as a viable approach for Natural Product lead optimisation to a development candidate. Due to their intrinsic structural diversity and assembly-line-like biosynthesis, polyketides are particularly appropriate for this approach, but other Natural Products, such as peptides, are also suitable.

For thousands of years, natural products have played an important role throughout the world in treating and preventing human diseases. Historically, the majority of new drugs have been generated from natural products (secondary metabolites) and from compounds derived from natural products. During the past 15 years, Pharmaceutical industry research into natural products has declined, in part because of an emphasis on high-throughput screening of synthetic libraries. Currently there is substantial decline in new drug approvals and impending loss of patent protection for important medicines. However, untapped biological resources, “smart screening” methods, robotic separation with structural analysis, metabolic engineering, and synthetic biology offer exciting technologies for new natural product drug discovery. Advances in rapid genetic sequencing, coupled with manipulation of biosynthetic pathways, may provide a vast resource for the future discovery of pharmaceutical agents.

There is a current trend of discovery and applications of bioactive agents from natural sources. According to Grabley and Thiericke (Grabley and Thiericke, 1999), natural products account for 30% of international drug sales. Although recombinant proteins and peptides have been accounting for an increasing amount of sales, the superiority of low-molecular mass compounds in human disease therapy remains undisputed, mainly due to more favorable compliance and bioavailability. To meet the demand for the thousands of test samples that must be submitted for highthroughput screening (HTS), it is essential to successfully compete with the rigors of combinatorial chemistry by developing new strategies in natural product chemistry. HTS enables the testing of a large number of samples. Therefore, new concepts that can generate large collection of compounds that possess improved structural diversity are desirable. In the historical context and as a brief background, the discovery of antibiotics clearly ushered in a new approach for treating patients. It was entirely fortuitous—a byproduct of serendipity, a circumstance that scientists yearn for but from which they often do not benefit. In many respects, a template for complementary and alternative medicine (CAM) was being formed. Unlike this valuable discovery, and the currently emerging paradigm, the world of natural products has been awaiting more beneficial exploitation for several millennia. After all, what were people using as remedies. 


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