Explainable artificial intelligence in the design of selective carbonic anhydrase I-II inhibitors via molecular fingerprinting.

Autor: Kırboğa KK; Faculty of Engineering, Department of Bioengineering, Bilecik Seyh Edebali University, Bilecik, Turkey.; Bioengineering Department, Süleyman Demirel University, Isparta, Turkey., Işık M; Faculty of Engineering, Department of Bioengineering, Bilecik Seyh Edebali University, Bilecik, Turkey.
Jazyk: angličtina
Zdroj: Journal of computational chemistry [J Comput Chem] 2024 Jul 05; Vol. 45 (18), pp. 1530-1539. Date of Electronic Publication: 2024 Mar 15.
DOI: 10.1002/jcc.27335
Abstrakt: Inhibiting the enzymes carbonic anhydrase I (CA I) and carbonic anhydrase II (CA II) presents a potential avenue for addressing nervous system ailments such as glaucoma and Alzheimer's disease. Our study explored harnessing explainable artificial intelligence (XAI) to unveil the molecular traits inherent in CA I and CA II inhibitors. The PubChem molecular fingerprints of these inhibitors, sourced from the ChEMBL database, were subjected to detailed XAI analysis. The study encompassed training 10 regression models using IC 50 values, and their efficacy was gauged using metrics including R 2 , RMSE, and time taken. The Decision Tree Regressor algorithm emerged as the optimal performer (R 2 : 0.93, RMSE: 0.43, time-taken: 0.07). Furthermore, the PFI method unveiled key molecular features for CA I inhibitors, notably PubChemFP432 (C(O)N) and PubChemFP6978 (C(O)O). The SHAP analysis highlighted the significance of attributes like PubChemFP539 (C(O)NCC), PubChemFP601 (C(O)OCC), and PubChemFP432 (C(O)N) in CA I inhibitiotable n. Likewise, features for CA II inhibitors encompassed PubChemFP528(C(O)OCCN), PubChemFP791 (C(O)OCCC), PubChemFP696 (C(O)OCCCC), PubChemFP335 (C(O)NCCN), PubChemFP580 (C(O)NCCCN), and PubChemFP180 (C(O)NCCC), identified through SHAP analysis. The sulfonamide group (S), aromatic ring (A), and hydrogen bonding group (H) exert a substantial impact on CA I and CA II enzyme activities and IC 50 values through the XAI approach. These insights into the CA I and CA II inhibitors are poised to guide future drug discovery efforts, serving as a beacon for innovative therapeutic interventions.
(© 2024 Wiley Periodicals LLC.)
Databáze: MEDLINE
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