IMPPAT 2.0: An Enhanced and Expanded Phytochemical Atlas of Indian Medicinal Plants

ACS Omega, Год журнала: 2023, Номер 8(9), С. 8827 - 8845

Опубликована: Фев. 23, 2023

Compilation, curation, digitization, and exploration of the phytochemical space Indian medicinal plants can expedite ongoing efforts toward natural product traditional knowledge based drug discovery. To this end, we present IMPPAT 2.0, an enhanced expanded database compiling manually curated information on 4010 plants, 17,967 phytochemicals, 1095 therapeutic uses. Notably, 2.0 compiles associations at level plant parts provides a FAIR-compliant nonredundant in silico stereo-aware library phytochemicals from plants. The has been annotated with several useful properties to enable easier chemical space. We have also filtered subset 1335 drug-like which majority no similarity existing approved drugs. Using cheminformatics, characterized molecular complexity scaffold structural diversity performed comparative analysis other libraries. Altogether, is extensive atlas that accessible https://cb.imsc.res.in/imppat/.

Язык: Английский

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Macrocycles in Drug Discovery─Learning from the Past for the Future

Journal of Medicinal Chemistry, Год журнала: 2023, Номер 66(8), С. 5377 - 5396

Опубликована: Апрель 5, 2023

We have analyzed FDA-approved macrocyclic drugs, clinical candidates, and the recent literature to understand how macrocycles are used in drug discovery. Current drugs mainly infectious disease oncology, while oncology is major indication for candidates Most bind targets that difficult binding sites. Natural products provided 80–90% of whereas ChEMBL less complex structures. Macrocycles usually reside beyond Rule 5 chemical space, but 30–40% orally bioavailable. Simple bi-descriptor models, i.e., HBD ≤ 7 combination with either MW < 1000 Da or cLogP > 2.5, distinguished orals from parenterals can be as filters design. propose breakthroughs conformational analysis inspiration natural will further improve de novo design macrocycles.

Язык: Английский

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Modeling the expansion of virtual screening libraries

Nature Chemical Biology, Год журнала: 2023, Номер 19(6), С. 712 - 718

Опубликована: Янв. 16, 2023

Язык: Английский

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Programming inactive RNA-binding small molecules into bioactive degraders

Nature, Год журнала: 2023, Номер 618(7963), С. 169 - 179

Опубликована: Май 24, 2023

Abstract Target occupancy is often insufficient to elicit biological activity, particularly for RNA, compounded by the longstanding challenges surrounding molecular recognition of RNA structures small molecules. Here we studied patterns between a natural-product-inspired small-molecule collection and three-dimensionally folded structures. Mapping these interaction landscapes across human transcriptome defined structure–activity relationships. Although RNA-binding compounds that bind functional sites were expected response, most identified interactions predicted be biologically inert as they elsewhere. We reasoned that, such cases, an alternative strategy modulate biology cleave target through ribonuclease-targeting chimera, where molecule appended heterocycle binds locally activates RNase L 1 . Overlay substrate specificity with binding landscape molecules revealed many favourable candidate binders might bioactive when converted into degraders. provide proof concept, designing selective degraders precursor disease-associated microRNA-155 (pre-miR-155), JUN mRNA MYC mRNA. Thus, RNA-targeted degradation can leveraged convert strong, yet inactive, potent specific modulators function.

Язык: Английский

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Expanding chemistry through in vitro and in vivo biocatalysis

Nature, Год журнала: 2024, Номер 631(8019), С. 37 - 48

Опубликована: Июль 3, 2024

Язык: Английский

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The Time and Place for Nature in Drug Discovery

JACS Au, Год журнала: 2022, Номер 2(11), С. 2400 - 2416

Опубликована: Окт. 14, 2022

The case for a renewed focus on Nature in drug discovery is reviewed; not terms of natural product screening, but how and why biomimetic molecules, especially those produced by processes, should deliver the age artificial intelligence screening vast collections both vitro silico. declining product-likeness licensed drugs consequent physicochemical implications this trend context current practices are noted. To arrest these trends, logic seeking new bioactive agents with enhanced mimicry considered; notably that molecules constructed proteins (enzymes) more likely to interact other (e.g., targets transporters), notion validated products. Nature's finite number building blocks their interactions necessarily reduce potential numbers structures, yet enable expansion chemical space inherent diversity physical characteristics, pertinent property-based design. feasible variations motifs considered expanded encompass pseudo-natural products, leading further logical step harnessing bioprocessing routes access them. Together, offer opportunities enhancing mimicry, thereby bringing innovation synthesis exploiting characteristics recognition processes. computational guidance help identifying binding commonalities route map opportunity design tailored "organic/biological" rather than purely "synthetic" structures. prototype structures pay dividends disposition efficacy while inherently enabling greener sustainable manufacturing techniques.

Язык: Английский

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Chemical Multiverse: An Expanded View of Chemical Space

Molecular Informatics, Год журнала: 2022, Номер 41(11)

Опубликована: Авг. 2, 2022

Technological advances and practical applications of the chemical space concept in drug discovery, natural product research, other research areas have attracted scientific community's attention. The large- ultra-large spaces are associated with significant increase number compounds that can potentially be made exist increasing experimental calculated descriptors, emerging encode molecular structure and/or property aspects molecules. Due to importance continued evolution compound libraries, herein, we discuss definitions proposed literature for emphasize convenience, discussed use complementary descriptors obtain a comprehensive view data sets. In this regard, introduce term multiverse refer analysis sets through several spaces, each defined by different set representations. is contrasted related idea: consensus space.

Язык: Английский

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Discovery of a Drug-like, Natural Product-Inspired DCAF11 Ligand Chemotype

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Ноя. 30, 2023

Targeted proteasomal and autophagic protein degradation, often employing bifunctional modalities, is a new paradigm for modulation of function. In an attempt to explore degradation by means autophagy we combine arylidene-indolinones reported bind the autophagy-related LC3B-protein ligands PDEδ lipoprotein chaperone, BRD2/3/4-bromodomain containing proteins BTK- BLK kinases. Unexpectedly, resulting degraders do not induce macroautophagy, but instead direct their targets ubiquitin-proteasome system. Target mechanism identification reveal that covalently DCAF11, substrate receptor in CUL4A/B-RBX1-DDB1-DCAF11 E3 ligase. The tempered α, β-unsaturated indolinone electrophiles define drug-like DCAF11-ligand class enables exploration this ligase chemical biology medicinal chemistry programs. arylidene-indolinone scaffold frequently occurs natural products which raises question whether ligand classes can be found more widely among related compounds.

Язык: Английский

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Natural Products Have Increased Rates of Clinical Trial Success throughout the Drug Development Process

Journal of Natural Products, Год журнала: 2024, Номер 87(7), С. 1844 - 1851

Опубликована: Июль 6, 2024

Natural products (NPs) or their derivatives represent a large proportion of drugs that successfully progress through clinical trials to approval. This study explores the presence NPs in both early- and late-stage drug discovery determine success rate, factors features natural contribute such success. As proxy for early development stages, we analyzed patent applications over several decades, finding consistent NP, NP-derived, synthetic-compound-based documents, with latter group outnumbering NP NP-derived ones (approximately 77% vs 23%). We next assessed trial data, where observed steady increase compounds from phases I III (from approximately 35% phase 45% III), an inverse trend synthetics 65% 55% III). Finally, vitro silico toxicity studies revealed were less toxic alternatives synthetic counterparts. These discoveries offer valuable insights successful NP-based development, highlighting potential benefits prioritizing as starting points.

Язык: Английский

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Coumarins as versatile therapeutic phytomolecules: A systematic review

Phytomedicine, Год журнала: 2024, Номер 134, С. 155972 - 155972

Опубликована: Авг. 30, 2024

Язык: Английский

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