Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19.

We present a supercomputer-driven pipeline for in silico drug discovery using enhanced sampling molecular dynamics (MD) and ensemble docking. Ensemble docking makes use of MD results by docking compound databases into representative protein binding-site conformations, thus taking into account the dynamic properties of the binding sites. We also describe preliminary results obtained for 24 systems involving eight proteins of the proteome of SARS-CoV-2. The MD involves temperature replica exchange enhanced sampling, making use of massively parallel supercomputing to quickly sample the configurational space of protein drug targets. Using the Summit supercomputer at the Oak Ridge National Laboratory, more than 1 ms of enhanced sampling MD can be generated per day. We have ensemble docked repurposing databases to 10 configurations of each of the 24 SARS-CoV-2 systems using AutoDock Vina. Comparison to experiment demonstrates remarkably high hit rates for the top scoring tranches of compounds identified by our ensemble approach. We also demonstrate that, using Autodock-GPU on Summit, it is possible to perform exhaustive docking of one billion compounds in under 24 h. Finally, we discuss preliminary results and planned improvements to the pipeline, including the use of quantum mechanical (QM), machine learning, and artificial intelligence (AI) methods to cluster MD trajectories and rescore docking poses.

Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19.

We present a supercomputer-driven pipeline for in-silico drug discovery using enhanced sampling molecular dynamics (MD) and ensemble docking. We also describe preliminary results obtained for 23 systems involving eight protein targets of the proteome of SARS CoV-2. THe MD performed is temperature replica-exchange enhanced sampling, making use of the massively parallel supercomputing on the SUMMIT supercomputer at Oak Ridge National Laboratory, with which more than 1ms of enhanced sampling MD can be generated per day. We have ensemble docked repurposing databases to ten configurations of each of the 23 SARS CoV-2 systems using AutoDock Vina. We also demonstrate that using Autodock-GPU on SUMMIT, it is possible to perform exhaustive docking of one billion compounds in under 24 hours. Finally, we discuss preliminary results and planned improvements to the pipeline, including the use of quantum mechanical (QM), machine learning, and AI methods to cluster MD trajectories and rescore docking poses.

Perplexing pleural effusion.

Twenty-seven patients with perplexing pleural effusion were studied to determine clinical outcome. The value of performing pleuroscopic examination or open pleural biopsy (or both) in search of a diagnosis was assessed. After a mean follow-up period of six months, a diagnosis was reached in 16 patients, while 11 patients had no diagnosis after a mean follow-up period of 24 months. The causes for the effusions were neoplasm (eight patients), tuberculosis (one patient), blastomycosis (one patient), systemic lupus erythematosus (one patient), pulmonary infarction (two patients), and fractures of the ribs (three patients). The diagnosis was made by pleuroscopic examination or open biopsy in five patients, by autopsy in four, and by long-term follow-up studies in seven patients. When neoplasm or granulomatous disease was not suspected before surgery, pleuroscopic examination or open biopsy or both were nondiagnostic. These data support a policy of selecting patients for these procedures when a presumptive diagnosis of neoplasm or granulomatous disease is made but cannot be confirmed by less invasive methods. When the clinical data are too nonspecific to formulate a meaningful clinical impression, a more conservative approach is recommended.

Shifting tuberculosis care to the general hospital.

Control of tuberculosis infection within the hospital is of major importance to general hospitals that assume the responsibility for providing tuberculous patients with primary care services. Because patients vary in their potential infectiousness, each patient's disease should be assessed individually. Patients who have completed a prescribed course of treatment are not infectious, and no precautionary measures are indicated. Patients with positive sputum who are receiving chemotherapy are rarely infectious, but they should be lodged in a room with air control. Effective antituberculous chemotherapy and adequate ventilation of the environment are the most important means of achieving infection control. Each hospital should have an infection control committee that is responsible for implementing infection control policies and for ensuring that patients with tuberculosis receive high-quality medical care. Educating personnel about tuberculosis, providing necessary consultation services, and making sure that patients are referred properly at discharge are important functions of the committee. Only those hospitals that are willing to meet these minimum standards should assume this responsibility.