Exploiting Solvent Exposed Salt-Bridge Interactions for the Discovery of Potent Inhibitors of SOS1 Using Free-Energy Perturbation Simulations DOI
Abba E. Leffler,

Evelyne M. Houang,

Felicia Gray

и другие.

ACS Medicinal Chemistry Letters, Год журнала: 2025, Номер 16(3), С. 444 - 453

Опубликована: Фев. 28, 2025

Small molecules that bind the Son of Sevenless 1 protein (SOS1), thereby preventing activation RAS, have been widely pursued as a means for cell proliferation inhibition and antitumor activity. Guided by free-energy perturbation (FEP+) simulations, we discovered two acidic residues on perimeter known small molecule binding site SOS1, E906 E909, constitute potency handle can improve inhibitor affinity much 750-fold when targeted with basic groups to form salt bridges, despite being solvent exposed. Structure–Activity Relationship (SAR) X-ray crystallographic studies demonstrate this effect is attributable electrostatic interaction between ligand. This could be repurposed create new SOS1 inhibitors, documenting its general utility core exploration. Additional recent examples in literature suggest phenomenon may applicable number target classes are highlighted herein.

Язык: Английский

Nonpeptidic Irreversible Inhibitors of SARS-CoV-2 Main Protease with Potent Antiviral Activity DOI
Angelo Oneto, Ghazl Al Hamwi, Laura Schäkel

и другие.

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(17), С. 14986 - 15011

Опубликована: Авг. 15, 2024

SARS-CoV-2 infections pose a high risk for vulnerable patients. In this study, we designed benzoic acid halopyridyl esters bearing variety of substituents as irreversible inhibitors the main viral protease (Mpro). Altogether, 55 benzoyl chloro/bromo-pyridyl were synthesized, with broad variation substitution pattern on moiety. A workflow was employed multiparametric optimization, including Mpro inhibition assays and related pathogenic coronaviruses, duration enzyme inhibition, compounds' stability versus glutathione, cytotoxicity, antiviral activity. Several compounds showed IC50 values in low nanomolar range, kinact/Ki >100,000 M–1 s–1 High-resolution X-ray cocrystal structures indicated an important role ortho-fluorobenzoyl substitution, forming water network that stabilizes inhibitor-bound enzyme. The most potent compound p-ethoxy-o-fluorobenzoyl chloropyridyl ester (PSB-21110, 29b, MW 296 g/mol; EC50 2.68 nM), which may serve lead structure broad-spectrum anticoronaviral therapeutics.

Язык: Английский

Процитировано

4
Exploiting Solvent Exposed Salt-Bridge Interactions for the Discovery of Potent Inhibitors of SOS1 Using Free-Energy Perturbation Simulations DOI
Abba E. Leffler,

Evelyne M. Houang,

Felicia Gray

и другие.

ACS Medicinal Chemistry Letters, Год журнала: 2025, Номер 16(3), С. 444 - 453

Опубликована: Фев. 28, 2025

Small molecules that bind the Son of Sevenless 1 protein (SOS1), thereby preventing activation RAS, have been widely pursued as a means for cell proliferation inhibition and antitumor activity. Guided by free-energy perturbation (FEP+) simulations, we discovered two acidic residues on perimeter known small molecule binding site SOS1, E906 E909, constitute potency handle can improve inhibitor affinity much 750-fold when targeted with basic groups to form salt bridges, despite being solvent exposed. Structure–Activity Relationship (SAR) X-ray crystallographic studies demonstrate this effect is attributable electrostatic interaction between ligand. This could be repurposed create new SOS1 inhibitors, documenting its general utility core exploration. Additional recent examples in literature suggest phenomenon may applicable number target classes are highlighted herein.

Язык: Английский

Процитировано

0