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.

Functional analysis and treatment of problem behavior evoked by noise.

We conducted a four-part investigation to develop methods for assessing and treating problem behavior evoked by noise. In Phase 1, 7 participants with developmental disabilities who were described as being hypersensitive to specific noises were exposed to a series of noises under controlled conditions. Results for 2 of the participants verified that noise was apparently an aversive event. In Phase 2, results of functional analyses indicated that these 2 participants' problem behaviors were maintained by escape from noise. In Phase 3, preference assessments were conducted to identify reinforcers that might be used during treatment. Finally, in Phase 4, the 2 participants' problem behaviors were successfully treated with extinction, stimulus fading, and a differential-reinforcement-of-other-behavior (DRO) contingency (only 1 participant required DRO). Treatment effects for both participants generalized to their home environments and were maintained during a follow-up assessment. Procedures and results were discussed in terms of their relevance to the systematic assessment of noise as an establishing operation (EO) and, more generally, to the identification of idiosyncratic EO influences on behavior.

A functional analysis of hair pulling.

We experimentally assessed the functions of hair pulling and hair manipulation of a 19-year-old woman (Kris) with moderate mental retardation and cerebral palsy. In Phase 1 a functional analysis revealed that Kris pulled and manipulated hair for the greatest amount of time in the alone condition, suggesting that the behaviors were maintained by some form of automatic reinforcement (Vaughan & Michael, 1982). In Phase 2 we assessed the nature of the sensory stimulation that maintained hair pulling by providing continuous access to previously pulled or cut hair and, thereafter, by having Kris wear a rubber glove. The results suggested that hair pulling was maintained by digital-tactile stimulation (automatic positive reinforcement). These findings are discussed, and recommendations for further analyses of automatically reinforced habit behaviors are provided.

Augmenting simplified habit reversal in the treatment of oral-digital habits exhibited by individuals with mental retardation.

We investigated whether a simplified habit reversal treatment eliminates fingernail biting and related oral-digital habits exhibited by individuals with mild to moderate mental retardation. Although simplified habit reversal did little to decrease the target behaviors for 3 of 4 participants, simplified habit reversal plus additional treatment procedures decreased the behavior to near-zero levels for all participants. These procedures included remote prompting, remote contingencies involving differential reinforcement plus response cost, and differential reinforcement of nail growth. Limitations of habit reversal for individuals with mental retardation along with directions for future research involving therapist-mediated treatment procedures, particularly those involving remote prompting and remote contingencies, are discussed.

Analysis and treatment of finger sucking.

We analyzed and treated the finger sucking of 2 developmentally typical children aged 7 and 10 years. The functional analysis revealed that the finger sucking of both children was exhibited primarily during alone conditions, suggesting that the behavior was maintained by automatic reinforcement. An extended analysis provided support for this hypothesis and demonstrated that attenuation of stimulation produced by the finger sucking resulted in behavior reductions for both children. Treatment consisted of having each child wear a glove on the relevant hand during periods when he or she was alone. Use of the glove produced zero levels of finger sucking for 1 participant, whereas only moderate reductions were obtained for the other. Subsequently, an awareness enhancement device was used that produced an immediate reduction in finger sucking.

Training and generalization of sexual abuse prevention skills for women with mental retardation.

Previous research has shown that behavioral skills training to teach sexual abuse prevention skills to women with mental retardation results in skill acquisition but poor generalization. In this investigation we evaluated procedures for enhancing generalization following training. Five women with mental retardation received 10 behavioral skills training sessions followed by in situ training when the skills did not fully generalize. Behavioral skills training resulted in skill acquisition and in situ training produced generalized responding during naturalistic assessments.