Artificial intelligence uncovers carcinogenic human metabolites.

The genome of a eukaryotic cell is often vulnerable to both intrinsic and extrinsic threats owing to its constant exposure to a myriad of heterogeneous compounds. Despite the availability of innate DNA damage responses, some genomic lesions trigger malignant transformation of cells. Accurate prediction of carcinogens is an ever-challenging task owing to the limited information about bona fide (non-)carcinogens. We developed Metabokiller, an ensemble classifier that accurately recognizes carcinogens by quantitatively assessing their electrophilicity, their potential to induce proliferation, oxidative stress, genomic instability, epigenome alterations, and anti-apoptotic response. Concomitant with the carcinogenicity prediction, Metabokiller is fully interpretable and outperforms existing best-practice methods for carcinogenicity prediction. Metabokiller unraveled potential carcinogenic human metabolites. To cross-validate Metabokiller predictions, we performed multiple functional assays using Saccharomyces cerevisiae and human cells with two Metabokiller-flagged human metabolites, namely 4-nitrocatechol and 3,4-dihydroxyphenylacetic acid, and observed high synergy between Metabokiller predictions and experimental validations.

OdoriFy: A conglomerate of artificial intelligence-driven prediction engines for olfactory decoding.

The molecular mechanisms of olfaction, or the sense of smell, are relatively underexplored compared with other sensory systems, primarily because of its underlying molecular complexity and the limited availability of dedicated predictive computational tools. Odorant receptors (ORs) allow the detection and discrimination of a myriad of odorant molecules and therefore mediate the first step of the olfactory signaling cascade. To date, odorant (or agonist) information for the majority of these receptors is still unknown, limiting our understanding of their functional relevance in odor-induced behavioral responses. In this study, we introduce OdoriFy, a Web server featuring powerful deep neural network-based prediction engines. OdoriFy enables (1) identification of odorant molecules for wildtype or mutant human ORs (Odor Finder); (2) classification of user-provided chemicals as odorants/nonodorants (Odorant Predictor); (3) identification of responsive ORs for a query odorant (OR Finder); and (4) interaction validation using Odorant-OR Pair Analysis. In addition, OdoriFy provides the rationale behind every prediction it makes by leveraging explainable artificial intelligence. This module highlights the basis of the prediction of odorants/nonodorants at atomic resolution and for the ORs at amino acid levels. A key distinguishing feature of OdoriFy is that it is built on a comprehensive repertoire of manually curated information of human ORs with their known agonists and nonagonists, making it a highly interactive and resource-enriched Web server. Moreover, comparative analysis of OdoriFy predictions with an alternative structure-based ligand interaction method revealed comparable results. OdoriFy is available freely as a web service at https://odorify.ahujalab.iiitd.edu.in/olfy/.