A Multidirectional Molecular Targets-basedApproach for New Antiparasitic Drug Discovery from Natural Products Resources

Natural products derived from plants, microbial organisms as well as marine flora & fauna are unmatched source for new drugs for the treatment of many maladies, particularly infectious diseases and cancer. However, technical complexities associated with natural product research, emergence of high throughput screening, and combinatorial chemistry technologies resulted in a diminished interest in natural products sources for new drug discovery. Limitations of success of these technologies and elimination of technical impediments on separation, purification and structure elucidation of natural compounds have renewed interest in nature as a source of new drugs. The laboratories working on natural products-based drug discovery programs have mostly relied on a traditional approach of random screening and bioassay-guided fractionation. Modern drug discovery programs have greatly benefited from a number of recent scientific and technological advancements, including the rapid identification of diverse new targets through genomics, bioinformatics and proteomics. Availability of annotated genome maps and large number of validated chemotherapeutic targets have fostered a paradigm shift in new drug discovery approaches. A multidirectional, molecular target-based approach has been adopted for new natural products drug discovery, particularly against the tropical parasitic diseases. This involves screening of natural compound libraries through a battery of validated target enzymes, screening of selective compound libraries likely to act on specific target enzyme/pathways, and use of natural product lead compounds with novel pharmacophores to probe the chemotherapeutic targets. Terpenoids and isoprenoids are highly abundant in natural resources, and may target the unique non-mavelonate pathway of isoprenoid biosynthesis & protein prenylation functions in parasitic protozoa; these may be a useful source for generating lead antiparasitic agents. Natural and semisynthetic organosulfur compound libraries, selected as the potential inhibitors of glutathione- and cysteine-dependent antioxidant defense functions, have also yielded potential antiparasitic lead molecules. Discovery of apicoplast and plant-like metabolic pathways in apicomplexan parasites have led to assessment of natural phytotoxic molecules and herbicides as potential antiparasitic agents. Several natural products with novel pharmacophore structures have been identified as new antiparasitic leads. Manzamine A, a marine antiparasitic alkaloid and gossypol were employed to probe the potential drug targets in the parasites and have provided useful insights. The multidirectional molecular targets-based approach has complemented conventional approaches for discovery of new natural product antiparasitic agents and identification of novel chemotherapeutic targets. Similar approaches may also be applied to new natural product drug discovery research against other diseases.