Details

Autor(en) / Beteiligte

• Karasev, Dmitry A.
• Sobolev, Boris N.
• Filimonov, Dmitry A.
• Lagunin, Alexey

Titel

Prediction of viral protease inhibitors using proteochemometrics approach

Ist Teil von

• Computational biology and chemistry, 2024-06, Vol.110, p.108061-108061, Article 108061

Ort / Verlag

England: Elsevier Ltd

Erscheinungsjahr

2024

Quelle

MEDLINE

Beschreibungen/Notizen

• Being widely accepted tools in computational drug search, the (Q)SAR methods have limitations related to data incompleteness. The proteochemometrics (PCM) approach expands the applicability area by using description for both protein and ligand structures. The PCM algorithms are urgently required for the development of new antiviral agents. We suggest the PCM method using the TLMNA descriptors, combining the MNA descriptors of ligands and protein sequence N-grams. Our method was validated on the viral chymotrypsin-like proteases and their ligands. We have developed an original protocol allowing us to collect a comprehensive set of 15 protein sequences and more than 9000 ligands from the ChEMBL database. The N-grams were derived from the 3D-based alignment, accurately superposing ligand-binding regions. In testing the ligand set in SAR mode with MNA descriptors, an accuracy above 0.95 was determined that shows the perspective of the antiviral drug search in virtual chemical libraries. The effective PCM models were built with the TLMNA descriptor. The strong validation procedure with pair exclusion simulated the prediction of interactions between the new ligands and new targets, resulting in accuracy estimation up to 0.89. The PCM approach shows slightly lower accuracy caused by more uncertainty compared with SAR, but it overcomes the problem of data incompleteness. [Display omitted] •A scheme for filtering data on protease inhibitors from the ChEMBL database has been proposed.•The original descriptors are based on the 3D alignment of proteins and structural descriptors of ligands.•The models have been obtained providing the reliable predictions of the ligands’ activity against new viral targets.