Molecular dynamics analysis of a flexible loop at the binding interface of the SARS-CoV-2 spike protein receptor-binding domain.

Since the identification of the SARS-CoV-2 virus as the causative agent of the current COVID-19 pandemic, considerable effort has been spent characterizing the interaction between the Spike protein receptor-binding domain (RBD) and the human angiotensin converting enzyme 2 (ACE2) receptor. This has provided a detailed picture of the end point structure of the RBD-ACE2 binding event, but what remains to be elucidated is the conformation and dynamics of the RBD prior to its interaction with ACE2. In this work, we utilize molecular dynamics simulations to probe the flexibility and conformational ensemble of the unbound state of the receptor-binding domain from SARS-CoV-2 and SARS-CoV. We have found that the unbound RBD has a localized region of dynamic flexibility in Loop 3 and that mutations identified during the COVID-19 pandemic in Loop 3 do not affect this flexibility. We use a loop-modeling protocol to generate and simulate novel conformations of the CoV2-RBD Loop 3 region that sample conformational space beyond the ACE2 bound crystal structure. This has allowed for the identification of interesting substates of the unbound RBD that are lower energy than the ACE2-bound conformation, and that block key residues along the ACE2 binding interface. These novel unbound substates may represent new targets for therapeutic design.

Evolution of the SARS-CoV-2 proteome in three dimensions (3D) during the first 6 months of the COVID-19 pandemic.

Understanding the molecular evolution of the SARS-CoV-2 virus as it continues to spread in communities around the globe is important for mitigation and future pandemic preparedness. Three-dimensional structures of SARS-CoV-2 proteins and those of other coronavirusess archived in the Protein Data Bank were used to analyze viral proteome evolution during the first 6 months of the COVID-19 pandemic. Analyses of spatial locations, chemical properties, and structural and energetic impacts of the observed amino acid changes in >48 000 viral isolates revealed how each one of 29 viral proteins have undergone amino acid changes. Catalytic residues in active sites and binding residues in protein-protein interfaces showed modest, but significant, numbers of substitutions, highlighting the mutational robustness of the viral proteome. Energetics calculations showed that the impact of substitutions on the thermodynamic stability of the proteome follows a universal bi-Gaussian distribution. Detailed results are presented for potential drug discovery targets and the four structural proteins that comprise the virion, highlighting substitutions with the potential to impact protein structure, enzyme activity, and protein-protein and protein-nucleic acid interfaces. Characterizing the evolution of the virus in three dimensions provides testable insights into viral protein function and should aid in structure-based drug discovery efforts as well as the prospective identification of amino acid substitutions with potential for drug resistance.

A Case of Aplastic Anemia Associated With Long-Term Metronidazole Use.

Metronidazole is a nitroimidazole antibacterial agent that is highly effective for the treatment of protozoal and anaerobic infections. Metronidazole is known to cause hematologic adverse effects, including a reversible mild neutropenia; in rare circumstances, thrombocytopenia has been associated with metronidazole treatment. We present a case of aplastic anemia related to the extended use of metronidazole.

Evolution of the SARS-CoV-2 proteome in three dimensions (3D) during the first six months of the COVID-19 pandemic.

Three-dimensional structures of SARS-CoV-2 and other coronaviral proteins archived in the Protein Data Bank were used to analyze viral proteome evolution during the first six months of the COVID-19 pandemic. Analyses of spatial locations, chemical properties, and structural and energetic impacts of the observed amino acid changes in >48,000 viral proteome sequences showed how each one of the 29 viral study proteins have undergone amino acid changes. Structural models computed for every unique sequence variant revealed that most substitutions map to protein surfaces and boundary layers with a minority affecting hydrophobic cores. Conservative changes were observed more frequently in cores versus boundary layers/surfaces. Active sites and protein-protein interfaces showed modest numbers of substitutions. Energetics calculations showed that the impact of substitutions on the thermodynamic stability of the proteome follows a universal bi-Gaussian distribution. Detailed results are presented for six drug discovery targets and four structural proteins comprising the virion, highlighting substitutions with the potential to impact protein structure, enzyme activity, and functional interfaces. Characterizing the evolution of the virus in three dimensions provides testable insights into viral protein function and should aid in structure-based drug discovery efforts as well as the prospective identification of amino acid substitutions with potential for drug resistance.

Patterns of Palliative Care Pharmacist Interventions and Outcomes as Part of Inpatient Palliative Care Consult Service.

INTRODUCTION: Palliative care uses a team approach, including physicians, nurses, social workers, chaplains, and pharmacists. The pharmacist's role within palliative care teams is increasing and initial favorable outcomes have been reported. METHODS: This retrospective study evaluated adult hospitalized patients seen by a part-time palliative care specialist pharmacist as part of the palliative care consultation team at an academic health system during a 15-month period between September 1, 2015, and March 30, 2017. Our study's objective is to identify patterns of an inpatient palliative care pharmacist's interventions and outcomes and evaluate the impact of pharmacist involvement on patient hospital length of stay (LOS), length from admission to palliative care consult (LTC), and time from consult to discharge or death (CTD). RESULTS: The palliative care pharmacist was on service 35% of the time and saw 26.4% of the patient seen by the palliative care team (n = 341 out of 1293). Each patient received an average of 3.5 interventions with an average of 4.1 documented outcomes. The most common interventions were optimizing palliative medication regimen and providing education; most common outcomes were implementation of a change in palliative medication regimen and education of healthcare professionals. Overall, patients seen by the palliative care pharmacist were younger (p < 0.05), more likely to be female (p < 0.05), and more likely to have a primary palliative consultation reason listed as "pain" (p < 0.005). LOS, LTC, and CTD were significantly longer for patients seen by palliative care pharmacist. CONCLUSION: Pharmacist interventions and outcomes were predominantly related to optimizing symptoms by changes in medication regimen and education of healthcare professionals. A subanalysis of patients with known date of first pharmacist visit found significantly improved LOS, LTC, and CTD for patients with early access to palliative pharmacy (in addition to the other members of the palliative team) compared to those without early access.