Discovery of highly potent phosphodiesterase-1 inhibitors by a combined-structure free energy perturbation approach.
10.1016/j.apsb.2024.06.021
- Author:
Zhe LI
1
;
Mei-Yan JIANG
1
;
Runduo LIU
1
;
Quan WANG
1
;
Qian ZHOU
1
;
Yi-You HUANG
1
;
Yinuo WU
1
;
Chang-Guo ZHAN
2
;
Hai-Bin LUO
1
Author Information
1. State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
2. Molecular Modeling and Biopharmaceutical Center and Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
- Publication Type:Journal Article
- Keywords:
Drug design;
Free energy perturbation;
Molecular simulation;
Phosphodiesterase 1;
Relative binding free energy
- From:
Acta Pharmaceutica Sinica B
2024;14(12):5357-5369
- CountryChina
- Language:English
-
Abstract:
Accurate receptor/ligand binding free energy calculations can greatly accelerate drug discovery by identifying highly potent ligands. By simulating the change from one compound structure to another, the relative binding free energy (RBFE) change can be calculated based on the theoretically rigorous free energy perturbation (FEP) method. However, existing FEP-RBFE approaches may face convergence challenges due to difficulties in simulating non-physical intermediate states, which can lead to increased computational costs to obtain the converged results. To fundamentally overcome these issues and accelerate drug discovery, a new combined-structure RBFE (CS-FEP) calculation strategy was proposed, which solved the existing issues by constructing a new alchemical pathway, smoothed the alchemical transformation, increased the phase-space overlap between adjacent states, and thus significantly increased the convergence and accelerated the relative binding free energy calculations. This method was extensively tested in a practical drug discovery effort by targeting phosphodiesterase-1 (PDE1). Starting from a PDE1 inhibitor (compound 9, IC50 = 16.8 μmol/L), the CS-FEP guided hit-to-lead optimizations resulted in a promising lead (11b and its mesylate salt formulation 11b-Mesylate, IC50 = 7.0 nmol/L), with ∼2400-fold improved inhibitory activity. Further experimental studies revealed that the lead showed reasonable metabolic stability and significant anti-fibrotic effects in vivo.
