How Carvedilol activates β-adrenoceptors.

Carvedilol is among the most effective β-blockers for improving survival after myocardial infarction. Yet the mechanisms by which carvedilol achieves this superior clinical profile are still unclear. Beyond blockade of β-adrenoceptors, arrestin-biased signalling via β-adrenoceptors is a molecular mechanism proposed to explain the survival benefits.

The Isoleucine at Position 118 in Transmembrane 2 Is Responsible for the Selectivity of Xamoterol, Nebivolol, and ICI89406 for the Human 1-Adrenoceptor.

Known off-target interactions frequently cause predictable drug side-effects (e.g., 1-antagonists used for heart disease, risk 2-mediated bronchospasm).

Hotspot Identification and Drug Design of Protein-Protein Interaction Modulators Using the Fragment Molecular Orbital Method.

Protein-protein interactions (PPIs) are essential for the function of many proteins. Aberrant PPIs have the potential to lead to disease, making PPIs promising targets for drug discovery. There are over 64,000 PPIs in the human interactome reference database; however, to date, very few PPI modulators have been approved for clinical use.

Calcium current modulation by the γ1 subunit depends on alternative splicing of CaV1.1.

The skeletal muscle voltage-gated calcium channel (CaV1.1) primarily functions as a voltage sensor for excitation-contraction coupling. Conversely, its ion-conducting function is modulated by multiple mechanisms within the pore-forming α1S subunit and the auxiliary α2δ-1 and γ1 subunits.

Fighting COVID-19 with Artificial Intelligence.

The development of vaccines for the treatment of COVID-19 is paving the way for new hope. Despite this, the risk of the virus mutating into a vaccine-resistant variant still persists. As a result, the demand of efficacious drugs to treat COVID-19 is still pertinent.

Ion-pair interactions between voltage-sensing domain IV and pore domain I regulate Ca1.1 gating.

The voltage-gated calcium channel Ca1.1 belongs to the family of pseudo-heterotetrameric cation channels, which are built of four structurally and functionally distinct voltage-sensing domains (VSDs) arranged around a common channel pore. Upon depolarization, positive gating charges in the S4 helices of each VSD are moved across the membrane electric field, thus generating the conformational change that prompts channel opening.

Inhibitors of Fumarylacetoacetate Hydrolase Domain Containing Protein 1 (FAHD1).

(FAHD1) acts as oxaloacetate decarboxylase in mitochondria, contributing to the regulation of the tricarboxylic acid cycle. Guided by a high-resolution X-ray structure of FAHD1 liganded by oxalate, the enzymatic mechanism of substrate processing is analyzed in detail. Taking the chemical features of the FAHD1 substrate oxaloacetate into account, the potential inhibitor structures are deduced.

Direct targeting of Gα and Gα oncoproteins in cancer cells.

Somatic gain-of-function mutations of and , which encode α subunits of heterotrimeric Gα proteins, occur in about 85% of cases of uveal melanoma (UM), the most common cancer of the adult eye. Molecular therapies to directly target these oncoproteins are lacking, and current treatment options rely on radiation, surgery, or inhibition of effector molecules downstream of these G proteins. A hallmark feature of oncogenic Gα proteins is their reduced intrinsic rate of hydrolysis of guanosine triphosphate (GTP), which results in their accumulation in the GTP-bound, active state.

Identification of dual Sigma1 receptor modulators/acetylcholinesterase inhibitors with antioxidant and neurotrophic properties, as neuroprotective agents.

In this manuscript we report on the design, synthesis and evaluation of dual Sigma 1 Receptor (S1R) modulators/Acetylcholinesterase (AChE) inhibitors endowed with antioxidant and neurotrophic properties, potentially able to counteract neurodegeneration. The compounds based on arylalkylaminoketone scaffold integrate the pharmacophoric elements of RRC-33, a S1R modulator developed by us, donepezil, a well-known AChE inhibitor, and curcumin, a natural antioxidant compound with neuroprotective properties. A small library of compounds was synthesized and preliminary in vitro screening performed.

Mechanisms Responsible for ω-Pore Currents in Ca Calcium Channel Voltage-Sensing Domains.

Mutations of positively charged amino acids in the S4 transmembrane segment of a voltage-gated ion channel form ion-conducting pathways through the voltage-sensing domain, named ω-current. Here, we used structure modeling and MD simulations to predict pathogenic ω-currents in Ca1.1 and Ca1.

Molecular Connectivity Predefines Polypharmacology: Aliphatic Rings, Chirality, and sp Centers Enhance Target Selectivity.

Dark chemical matter compounds are small molecules that have been recently identified as highly potent and selective hits. For this reason, they constitute a promising class of possible candidates in the process of drug discovery and raise the interest of the scientific community. To this purpose, Wassermann et al.

Gaining in pan-affinity towards sigma 1 and sigma 2 receptors. SAR studies on arylalkylamines.

Sigma Receptor (SR) modulators are involved in different signal transduction pathways, representing important pharmacological/therapeutic tools in several pathological conditions, such as neurodegenerative diseases and cancers. To this purpose, numerous compounds have been developed in order to target selectively one of the two subtypes (S1R and S2R) as chemotherapeutic agent. However, experiments have also shown that ligands which are able to bind both SR subtypes can be useful for the diagnosis and/or the treatment of cancers.

CACNA1D de novo mutations in autism spectrum disorders activate Cav1.3 L-type calcium channels.

Background: Cav1.3 voltage-gated L-type calcium channels (LTCCs) are part of postsynaptic neuronal signaling networks. They play a key role in brain function, including fear memory and emotional and drug-taking behaviors.