From atoms to cells: bridging the gap between potency, efficacy, and safety of small molecules directed at a membrane protein

Abstract

Membrane proteins constitute a substantial fraction of the human proteome, thus representing a vast source of therapeutic drug targets. Indeed, newly devised technologies now allow targeting "undruggable" regions of membrane proteins to modulate protein function in the cell. Despite the advances in technology, the rapid translation of basic science discoveries into potential drug candidates targeting transmembrane protein domains remains challenging. We address this issue by harmonizing single molecule-based and ensemble-based atomistic simulations of ligand-membrane interactions with patient-derived induced pluripotent stem cell (iPSC)-based experiments to gain insights into drug delivery, cellular efficacy, and safety of molecules directed at membrane proteins. In this study, we interrogated the pharmacological activation of the cardiac Ca2+ pump (Sarcoplasmic reticulum Ca2+-ATPase, SERCA2a) in human iPSC-derived cardiac cells as a proof-of-concept model. The combined computational-experimental approach serves as a platform to explain the differences in the cell-based activity of candidates with similar functional profiles, thus streamlining the identification of drug-like candidates that directly target SERCA2a activation in human cardiac cells. Systematic cell-based studies further showed that a direct SERCA2a activator does not induce cardiotoxic pro-arrhythmogenic events in human cardiac cells, demonstrating that pharmacological stimulation of SERCA2a activity is a safe therapeutic approach targeting the heart. Overall, this novel platform encompasses organ-specific drug potency, efficacy, and safety, and opens new avenues to accelerate the bench-to-patient research aimed at designing effective therapies directed at membrane protein domains.

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

“…Neuroleptics Trifluoperazine, Haloperidol decanoate, Clozapine, Quetiapine, Olanzapine, Aripiprazole, Amisulpride [323] Alzheimer disease Pregnanolone sulfate, Pregnanolone glutamate [324], Carbazoles [325] Anticonvulsant and muscle relaxant Carbamazepine [326][327][328], Nordazepam [199], Lamotrigine [199], Chlorzoxazone [132] Cardiac arrhythmias Dronedarone [312] P2Y1 antagonist BPTU [329] Urea cycle disorders 4-phenylbutyrate Immunosuppressant Cyclosporine A and E [330] Cardiac Ca 2+ pump inhibitors CDN1163, CP-154526, Ro 41-0960 [331] Eye drops components Cetalkonium chloride, Poloxamer 188 [332] Vaccine adjuvant Cobalt porphyrin phospholipid [333], Lipidated nicotine [334] Other potential drugs Baicalin [282], Emodin [282], Siramesine [335], HMI and HMI-1a3 [336], Peptide mimicking GM1 [337], AMG3 [338], 1,8-naphthyridine derivatives [339], Protein kinase inhibitors [340], Bile salt export pump inhibitors [341] Pulmonary surfactants form a complex structure on the inner lung surfaces, the alveoli, including the only monolayer in the human body at the boundary between the pulmonary liquids and air. For drugs designed to treat lung conditions that are delivered through pulmonary administration, e.g., corticosteroid and salbutamol inhalers for the treatment of asthma, this monolayer is the first barrier that they encounter.…”