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More recently, there has been a paradigm shift toward selective drug targeting in the treatment of neurological disorders, including drug addiction, schizophrenia, and Parkinson's disease mediated by the different dopamine receptor subtypes. Antagonists with higher selectivity for D3 dopamine receptor (D3DR) over D2 dopamine receptor (D2DR) have been shown to attenuate drug‐seeking behavior and associated side effects compared to non‐subtype selective antagonists. However, high conservations among constituent residues of both proteins, particularly at the ligand‐binding pockets, remain a challenge to therapeutic drug design. Recent studies have reported the discovery of two small‐molecules R‐VK4‐40 and Y‐QA31 which substantially inhibited D3DR with >180‐fold selectivity over D2DR. Therefore, in this study, we seek to provide molecular and structural insights into these differential binding mechanistic using meta‐analytic computational simulation methods. Findings revealed that R‐VK4‐40 and Y‐QA31 adopted shallow binding modes and were more surface‐exposed at D3DR while on the contrary, they exhibited deep hydrophobic pocket binding at D2DR. Also, two non‐conserved residues; Tyr361.39 and Ser18245.51 were identified in D3DR, based on their crucial roles and contributions to the selective binding of R‐VK4‐40 and Y‐QA31. Importantly, both antagonists exhibited high affinities in complex with D3DR compared to D2DR, while van der Waals energies contributed majorly to their binding and stability. Structural analyses also revealed the distinct stabilizing effects of both compounds on D3DR secondary architecture relative to D2DR. Therefore, findings herein pinpointed the origin and mechanistic of selectivity of the compounds, which may assist in the rational design of potential small molecules of the D2‐like dopamine family receptor subtype with improved potency and selectivity. [ABSTRACT FROM AUTHOR]

Today's device drivers are dependent on a given operating system, kernel, or an embedded system platform that provides a higher level of abstraction for its use. We present a USB mass storage device driver that does not depend on any operating system, or kernel, or embedded application. The device driver runs on a bare PC and directly interfaces with an application written in C/C++. The application programmer controls and manages all driver facilities. We describe a step-by-step approach to design the driver and provide code snippets of its key elements that can be used to build a device driver that runs on a bare PC, or a similar computing device. The bare PC API can be used to build a file management system that is independent of standard file system specifications. A bare device driver inherently provides simplicity, total control, flexibility, portability, platform independence, and better performance compared to a standard device driver. The performance measurements for read and write operations show a performance gain over a Linux system with significant improvements in stress tests. The experiments suggest that large transfers are optimized for groups consisting of a particular number of sectors. Bare device drivers can be used for building bare applications or as a foundation for building other types of USB drivers that can run directly on a variety of devices with no system support. [ABSTRACT FROM AUTHOR]

Dopamine receptors constitute a unique class of G‐protein coupled receptors that mediate the activities of dopamine, a neurotransmitter implicated in diverse neurological diseases when dysregulated. Over the years, antipsychotic drugs have been primarily directed towards D2 dopamine receptor (DRD2) while associable adverse effects have been centred on non‐selective targeting. The recent crystal structure of DRD2 in complex with atypical antipsychotic could further aid the structure‐based design of highly DRD2‐selective antipsychotics. Therefore, in this study, we comprehensively investigate the molecular recognition and differential binding landscapes of class‐I and II DRD2 atypical antipsychotics, using membrane‐bilayer molecular dynamics simulation and binding free energy techniques. Findings revealed that selected class‐I antipsychotics exhibited binding dynamics and poses dissimilar to the class‐II types with different interactive mechanisms at the binding cavity of DRD2. More interestingly, the class‐II drugs established a highly coordinated binding at the DRD2 active site with a pertinent and recurrent involvement of Asp114 via strong hydrogen interactions. Furthermore, while these compounds exert distinct effects on DRD2 structure, findings revealed that the class‐II types favourably engaged the deep hydrophobic pocket of DRD2 compared to the class‐I drugs. We speculate that these findings will be fundamental to the discovery of highly selective DRD2 antipsychotics. [ABSTRACT FROM AUTHOR]

More recently, there has been a paradigm shift toward selective drug targeting in the treatment of neurological disorders, including drug addiction, schizophrenia, and Parkinson's disease mediated by the different dopamine receptor subtypes. Antagonists with higher selectivity for D 3 dopamine receptor (D3DR) over D 2 dopamine receptor (D2DR) have been shown to attenuate drug-seeking behavior and associated side effects compared to non-subtype selective antagonists. However, high conservations among constituent residues of both proteins, particularly at the ligand-binding pockets, remain a challenge to therapeutic drug design. Recent studies have reported the discovery of two small-molecules R-VK4-40 and Y-QA31 which substantially inhibited D3DR with >180-fold selectivity over D2DR. Therefore, in this study, we seek to provide molecular and structural insights into these differential binding mechanistic using meta-analytic computational simulation methods. Findings revealed that R-VK4-40 and Y-QA31 adopted shallow binding modes and were more surface-exposed at D3DR while on the contrary, they exhibited deep hydrophobic pocket binding at D2DR. Also, two non-conserved residues; Tyr36 1.39 and Ser182 45.51 were identified in D3DR, based on their crucial roles and contributions to the selective binding of R-VK4-40 and Y-QA31. Importantly, both antagonists exhibited high affinities in complex with D3DR compared to D2DR, while van der Waals energies contributed majorly to their binding and stability. Structural analyses also revealed the distinct stabilizing effects of both compounds on D3DR secondary architecture relative to D2DR. Therefore, findings herein pinpointed the origin and mechanistic of selectivity of the compounds, which may assist in the rational design of potential small molecules of the D 2 -like dopamine family receptor subtype with improved potency and selectivity., (© 2021 John Wiley & Sons Ltd.)

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