TY  - JOUR
AB  - S. aureus resistant to methicillin (MRSA) is one of the most-concerned multidrug resistant bacteria, due to its role in life-threatening infections. There is an urgent need to develop new antibiotics against MRSA. In this study, we firstly compiled a data set of 2,3-diaminoquinoxalines by chemical synthesis and antibacterial screening against S. aureus, and then performed cheminformatics modeling and virtual screening. The compound with the Specs ID of AG-205/33156020 was discovered as a new antibacterial agent, and was further identified as a Gyrase B (GyrB) inhibitor. In light of the common features, we hypothesized that the 6c as the representative of 2,3-diaminoquinoxalines also inhibited GyrB and eventually proved it. Via molecular docking and molecular dynamics simulations, we identified binding modes of AG-205/33156020 and 6c to the ATPase domain of GyrB. Importantly, these GyrB inhibitors inhibited the MRSA strains and showed selectivity to HepG2 and HUVEC. Taken together, this research work provides an effective ligand-based computational workflow for scaffold hopping in anti-MRSA drug discovery, and discovers two new GyrB inhibitors that are worthy of further development.
AU  - Lian, X.*
AU  - Xia, Z.
AU  - Li, X.*
AU  - Karpov, P.
AU  - Jin, H.*
AU  - Tetko, I.V.
AU  - Xia, J.*
AU  - Wu, S.*
C1  - 62259
C2  - 50754
CY  - 525 B St, Ste 1900, San Diego, Ca 92101-4495 Usa
TI  - Anti-MRSA drug discovery by ligand-based virtual screening and biological evaluation.
JO  - Bioorg. Chem.
VL  - 114
PB  - Academic Press Inc Elsevier Science
PY  - 2021
SN  - 0045-2068
ER  - 

TY  - JOUR
AB  - A series of 2-aryl-2-(pyridin-2-yl)acetamides were synthesized and screened for their anticonvulsant activity in animal models of epilepsy. The compounds were broadly active in the 'classical' maximal electroshock seizure (MES) and subcutaneous Metrazol (scMET) tests as well as in the 6 Hz and kindling models of pharmacoresistant seizures. Furthermore, the compounds showed good therapeutic indices between anticonvulsant activity and motor impairment. Structure-activity relationship (SAR) trends clearly showed the highest activity resides in unsubstituted phenyl derivatives or compounds having ortho- and meta- substituents on the phenyl ring. The 2-aryl-2-(pyridin-2-yl)acetamides were derived by redesign of the cardiotoxic sodium channel blocker Disopyramide (DISO). Our results show that the compounds preserve the capability of the parent compound to inhibit voltage gated sodium currents in patch-clamp experiments; however, in contrast to DISO, a representative compound from the series 1 displays high levels of cardiac safety in a panel of in vitro and in vivo experiments.
AU  - Dawidowski, M.*
AU  - Król, M.*
AU  - Szulczyk, B.*
AU  - Chodkowski, A.*
AU  - Podsadni, P.*
AU  - Konopelski, P.*
AU  - Ufnal, M.*
AU  - Szuberski, P.*
AU  - Wróbel, M.Z.*
AU  - Zhang, Y.*
AU  - El Harchi, A.*
AU  - Hancox, J.C.*
AU  - Jarkovska, D.*
AU  - Mistrova, E.*
AU  - Sviglerova, J.*
AU  - Štengl, M.*
AU  - Popowicz, G.M.
AU  - Turło, J.*
C1  - 58602
C2  - 48499
CY  - 525 B St, Ste 1900, San Diego, Ca 92101-4495 Usa
TI  - Structure-activity relationship and cardiac safety of 2-aryl-2-(pyridin-2-yl) acetamides as a new class of broad-spectrum anticonvulsants derived from Disopyramide.
JO  - Bioorg. Chem.
VL  - 98
PB  - Academic Press Inc Elsevier Science
PY  - 2020
SN  - 0045-2068
ER  - 

TY  - JOUR
AB  - The cell-surface protein CD44, a primary receptor for hyaluronic acid (HA), is one of the most promising targets for cancer therapies. It is prominently involved in the process of tumor growth and metastasis. The possibility of modulating the CD44-HA interaction with a pharmacological inhibitor is therefore of great importance, yet until now there are only few small molecules reported to bind to CD44. Here, we describe the results of the NMR fragment-based screening conducted against CD44 by which we found eight new hit compounds that bind to the receptor with the affinity in milimolar range. The NMR-based characterization revealed that there are two possible binding modes for these compounds, and for some of them the binding is no longer possible in the presence of hyaluronic acid. This could provide an interesting starting point for the development of new high-affinity ligands targeting the CD44-HA axis.
AU  - Pustuła, M.*
AU  - Czub, M.*
AU  - Łabuzek, B.*
AU  - Surmiak, E.*
AU  - Tomala, M.*
AU  - Twarda-Clapa, A.*
AU  - Guzik, K.*
AU  - Popowicz, G.M.
AU  - Holak, T.A.*
C1  - 54664
C2  - 45754
CY  - 525 B St, Ste 1900, San Diego, Ca 92101-4495 Usa
SP  - 284-289
TI  - NMR fragment-based screening for development of the CD44-binding small molecules.
JO  - Bioorg. Chem.
VL  - 82
PB  - Academic Press Inc Elsevier Science
PY  - 2019
SN  - 0045-2068
ER  -