Calcium channel antagonists discovered by a multidisciplinary approach.
A multidisciplinary project has led to the discovery of novel, structurally diverse, L-type calcium entry blockers (CEBs). The absolute configuration of a recently reported CEB has been determined by vibrational circular dichroism spectroscopy, to assign the stereospecificity of the ligand-channel interaction. Thereafter, a virtual screening procedure was performed with the aim of identifying novel chemotypes for CEBs, starting from a database of purchasable compounds; 340,000 molecules were screened in silico in order to prioritize structures of interest for bioscreening. As a result, 20 compounds were tested in vitro, and functional and binding assays revealed several hits with promising behavior as CEBs.
Carosati
Emanuele
E
Dipartimento di Chimica, Università degli Studi di Perugia, Via Elce di Sotto 10, 06123 Perugia, Italy.
Cruciani
Gabriele
G
Chiarini
Alberto
A
Budriesi
Roberta
R
Ioan
Pierfranco
P
Spisani
Raffaella
R
Spinelli
Domenico
D
Cosimelli
Barbara
B
Fusi
Fabio
F
Frosini
Maria
M
Matucci
Rosanna
R
Gasparrini
Francesco
F
Ciogli
Alessia
A
Stephens
Philip J
PJ
Devlin
Frank J
FJ
D000818:Animals; D001665:Binding Sites; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects*; D002942:Circular Dichroism; D019992:Databases as Topic; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005260:Female; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D008024:Ligands; D015394:Molecular Structure; D009130:Muscle, Smooth / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology*; D010210:Papillary Muscles / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D008024:Ligands; D010069:Oxadiazoles