Target-based drug discovery through inversion of quantitative structure-drug-property relationships and molecular simulation: CA IX-sulphonamide complexes

Journal of Enzyme Inhibition and Medicinal Chemistry

Myunggi Yi¹  J. Jay Liu²  Ming Wah Wong³  Jonathan David³  Petar Žuvela⁴  Paweł P. Pomastowski⁵  Bogusław Buszewski⁶  Jarosław Sławiński⁷  Krzysztof Szafrański⁷  Beata Żołnowska⁷  Mariusz Belka⁸  Tomasz Bączek⁸  Claudiu T. Supuran⁹  Gulyaim Sagandykova^1,10 

[1] Department of Biomedical Engineering, Pukyong National University, Busan, Korea;Department of Chemical Engineering, Pukyong National University, Busan, Korea;Department of Chemistry, National University of Singapore, Singapore;Department of Chemistry, National University of Singapore, Singapore;Department of Environmental Chemistry and Bioanalytics, Faculty of Chemistry, Nicolaus Copernicus University, Toruń, Poland;Department of Environmental Chemistry and Bioanalytics, Faculty of Chemistry, Nicolaus Copernicus University, Toruń, Poland;Department of Environmental Chemistry and Bioanalytics, Faculty of Chemistry, Nicolaus Copernicus University, Toruń, Poland;Interdisciplinary Centre for Modern Technologies, Nicolaus Copernicus University, Toruń, Poland;Department of Organic Chemistry, Medical University of Gdańsk, Gdańsk, Poland;Department of Pharmaceutical Chemistry, Medical University of Gdańsk, Gdańsk, Poland;Dipartimento di Chimica, Universita degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Sesto Fiorentino (Florence), Italy;NEUROFARBA Department, Sezione di Scienze Farmaceutiche, Università degli Studi di Firenze, Sesto Fiorentino (Florence), Ital;Interdisciplinary Centre for Modern Technologies, Nicolaus Copernicus University, Toruń, Poland;

关键词: Drug discovery;    inverse QSPR;    molecular docking;    molecular dynamics;    carbonic anhydrases;   

DOI  :  10.1080/14756366.2018.1511551

来源: publisher

【 摘 要 】

In this work, a target-based drug screening method is proposed exploiting the synergy effect of ligand-based and structure-based computer-assisted drug design. The new method provides great flexibility in drug design and drug candidates with considerably lower risk in an efficient manner. As a model system, 45 sulphonamides (33 training, 12 testing ligands) in complex with carbonic anhydrase IX were used for development of quantitative structure-activity-lipophilicity (property)-relationships (QSPRs). For each ligand, nearly 5,000 molecular descriptors were calculated, while lipophilicity (logkw) and inhibitory activity (logKi) were used as drug properties. Genetic algorithm-partial least squares (GA-PLS) provided a QSPR model with high prediction capability employing only seven molecular descriptors. As a proof-of-concept, optimal drug structure was obtained by inverting the model with respect to reference drug properties. 3509 ligands were ranked accordingly. Top 10 ligands were further validated through molecular docking. Large-scale MD simulations were performed to test the stability of structures of selected ligands obtained through docking complemented with biophysical experiments.

【 授权许可】

CC BY