Hall 123

Pre synopsis seminar: Compilation, curation and exploration of natural product spaces to enable traditional knowledge based drug discovery

Vivek Ananth RP

IMSc, Chennai

This is a hybrid event and the zoom link to attend is:
zoom.us/j/92948173661
Meeting ID: 929 4817 3661
Passcode: 070112

Endogenous secondary metabolites produced by living organisms constitute a valuable natural product space. Such metabolites are primarily produced by plants, fungi and bacteria. Apart from being beneficial to the organism, many natural products have therapeutic activity. By one estimate nearly 34% of the approved drugs to date are either natural products or derived from them. Thus, natural product space is a biologically relevant chemical space of immense interest to researchers working in the field of drug discovery. Further, characterization and exploration of natural products from diverse origins such as bacteria, fungi, marine life, plants, etc. can enrich the natural product space. Specifically, medicinal plants and medicinal fungi have been used in traditional medicine across the world for treating many human ailments. In particular, mapping the natural product space of medicinal plants and medicinal fungi along with documentation of their therapeutic use will enable effective exploration of the biologically relevant and more likely therapeutic chemical space for drug discovery.

In the proposed thesis, for which this is a pre-synopsis submission talk, we focus on the compilation, curation and exploration of the natural product spaces of Indian medicinal plants and medicinal fungi to enable traditional knowledge based drug discovery. Specifically, we have built a comprehensive database, IMPPAT (version 1.0 and 2.0), on Indian Medicinal Plants, their Phytochemicals And Therapeutic uses, through literature mining followed by manual curation of information gathered from specialized books on traditional Indian medicine, published research articles and other existing online database resources. IMPPAT (2.0) compiles information on 4010 Indian medicinal plants, 17967 phytochemicals, 1095 therapeutic uses and 1133 traditional Indian medicinal formulations. It provides 3 types of associations for Indian medicinal plants: plant – part – phytochemicals, plant – part – therapeutic uses and plant – part – traditional medicinal formulations. Importantly, IMPPAT provides a FAIR compliant non-redundant in silico stereo-aware library of 17967 phytochemicals with 2D and 3D chemical structures. The phytochemical library has been annotated with several useful properties including predicted human target proteins to enable easier exploration of the chemical space. We also filtered a subset of 1335 drug-like phytochemicals of which the majority have no similarity to existing approved drugs. Using cheminformatics based analysis, we have characterized the molecular complexity and molecular scaffold based structural diversity of the phytochemical space of Indian medicinal plants, and performed a comparative analysis with other chemical libraries. Altogether, IMPPAT is the largest phytochemical atlas of Indian medicinal plants which is accessible at: cb.imsc.res.in/imppat/.

Similar to the creation of IMPPAT which provides the phytochemical space of Indian medicinal plants, we have also built Medicinal Fungi Secondary metabolites And Therapeutics (MeFSAT), a manually curated database of secondary metabolites in medicinal fungi. MeFSAT provided compiled and curated information on 184 medicinal fungi, 1830 secondary metabolites and 149 therapeutic uses obtained from published research articles and books. Importantly, MeFSAT also provides a non-redundant in silico natural product library of 1830 secondary metabolites along with information on their chemical structures. We find that secondary metabolites have high stereochemical complexity and shape complexity similar to other natural product libraries. Also using multiple drug-likeness rules, we have filtered a subset of 228 drug-like secondary metabolites in MeFSAT database. The compiled information in MeFSAT database can be openly accessed at: cb.imsc.res.in/mefsat/.

The thesis will lastly describe our research highlighting the biological application of the curated natural product space. Specifically, we have used the phytochemicals of Indian medicinal plants to identify potential phytochemical inhibitors of: (a) key host factors Transmembrane Protease Serine 2 (TMPRSS2) and cathepsin L which play an important role in SARS-CoV-2 host cell entry, and (b) ATP binding site of SARS-CoV-2 helicase Nsp13 which is a promising target for developing anti-COVID drugs.

In sum, the manually curated natural product spaces described in this thesis will enrich the known natural product space and will enable traditional knowledge based drug discovery.