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Nicotinic receptor pharmacology in silico: Insights and challenges.

ABSTRACT: Nicotinic acetylcholine receptors (nAChR) are homo- or hetero-pentameric ligand-gated ion channels of the Cys-loop superfamily and play important roles in the nervous system and muscles. Studies on nAChR benefit from in silico modeling due to the lack of high-resolution structures for most receptor subtypes and challenges in experiments addressing the complex mechanism of activation involving allosteric sites. Although there is myriad of computational modeling studies on nAChR, the multitude of the methods and parameters used in these studies makes modeling nAChR a daunting task, particularly for the non-experts in the field. To address this problem, the modeling literature on Torpedo nAChR and α7 nAChR were focused on as examples of heteromeric and homomeric nAChR, and the key in silico modeling studies between the years 1995-2019 were concisely reviewed. This was followed by a critical analysis of these studies by comparing the findings with each other and with the emerging experimental and computational data on nAChR. Based on these critical analyses, suggestions were made to guide the future researchers in the field of in silico modeling of nAChR. This article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology'.

SUBMITTER: Gulsevin A

PROVIDER: S-EPMC7898244 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Nicotinic receptor pharmacology in silico: Insights and challenges.

Gulsevin Alican A

Neuropharmacology 20200729

Nicotinic acetylcholine receptors (nAChR) are homo- or hetero-pentameric ligand-gated ion channels of the Cys-loop superfamily and play important roles in the nervous system and muscles. Studies on nAChR benefit from in silico modeling due to the lack of high-resolution structures for most receptor subtypes and challenges in experiments addressing the complex mechanism of activation involving allosteric sites. Although there is myriad of computational modeling studies on nAChR, the multitude of ...[more]

PMID: 32738311

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Project description:The neuronal alpha4beta2 nicotinic acetylcholine receptor (nAChR) is one of the most widely expressed nAChR subtypes in the brain. Its subunits have high sequence identity (54 and 46% for alpha4 and beta2, respectively) with alpha and beta subunits in Torpedo nAChR. Using the known structure of the Torpedo nAChR as a template, the closed-channel structure of the alpha4beta2 nAChR was constructed through homology modeling. Normal-mode analysis was performed on this closed structure and the resulting lowest frequency mode was applied to it for a "twist-to-open" motion, which increased the minimum pore radius from 2.7 to 3.4 A and generated an open-channel model. Nicotine could bind to the predicted agonist binding sites in the open-channel model but not in the closed one. Both models were subsequently equilibrated in a ternary lipid mixture via extensive molecular dynamics (MD) simulations. Over the course of 11 ns MD simulations, the open channel remained open with filled water, but the closed channel showed a much lower water density at its hydrophobic gate comprised of residues alpha4-V259 and alpha4-L263 and their homologous residues in the beta2 subunits. Brownian dynamics simulations of Na+ permeation through the open channel demonstrated a current-voltage relationship that was consistent with experimental data on the conducting state of alpha4beta2 nAChR. Besides establishment of the well-equilibrated closed- and open-channel alpha4beta2 structural models, the MD simulations on these models provided valuable insights into critical factors that potentially modulate channel gating. Rotation and tilting of TM2 helices led to changes in orientations of pore-lining residue side chains. Without concerted movement, the reorientation of one or two hydrophobic side chains could be enough for channel opening. The closed- and open-channel structures exhibited distinct patterns of electrostatic interactions at the interface of extracellular and transmembrane domains that might regulate the signal propagation of agonist binding to channel opening. A potential prominent role of the beta2 subunit in channel gating was also elucidated in the study.

Project description:BackgroundMedical students receive foundational knowledge in clinical pharmacology, bridging the gap between pharmacology and clinical practice. While several studies have investigated clinical pharmacology teaching methodologies, few describe the teaching and learning of clinical pharmacology in Saudi Arabia. This study aimed to explore medical students' preferences for teaching and learning methods in clinical pharmacology, identify current strengths and challenges, and provide suggestions for improvement.MethodsIn April 2024, a cross-sectional online survey was distributed via WhatsApp to second and third-year medical students at the University of Jeddah, KSA. The survey invitation explained the purpose, voluntary participation, and anonymity of responses, with informed consent obtained. A 24-item English questionnaire, including a Likert scale and open-ended questions, was developed and pilot-tested by five medical students. Data were analyzed using Minitab 17, employing descriptive statistics and Chi-square (χ2) tests to explore variable relationships.ResultsNinety out of 395 medical students completed the questionnaire, resulting in a 22.8% response rate. Students (43.3%, n = 39) found the curriculum comprehensive and relevant for medication management but lacked cohesiveness. Significant challenges included understanding course content (56.7%, n = 51) and passing exams (43.3%, n = 39). Additionally, 56.7% (n = 51) felt overwhelmed by the volume of information and struggled to apply pharmacological knowledge in practice. In terms of interactive teaching methods, such as case-based discussions and simulations, were found inadequate, and hands-on experience opportunities needed to be improved. While 43.3% (n = 39) expressed satisfaction with their clinical pharmacology education, 36.7% (n = 33) remained neutral, indicating uncertainty about the quality and effectiveness of the teaching they have received. Issues raised by students included feeling overwhelmed by the significant content in the curriculum (n = 62, 69.7%), and understanding the content (n = 51, 56.7%), demanding more case-based learning exercises with real-world patient scenarios (n = 47, 53.4%). For learning modalities, online modules and multimedia resources for self-paced learning were ranked highest (n = 37, 41%), followed by small-group discussions and case-based learning activities (n = 42, 46%).ConclusionsFindings suggest the need for more cohesive clinical pharmacology curricula, enhanced interactive teaching methods, and increased use of technology and practical applications to improve learning outcomes.

Dataset Information

Nicotinic receptor pharmacology in silico: Insights and challenges.

Publications

Nicotinic receptor pharmacology in silico: Insights and challenges.

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