Target identification for repurposed drugs active against SARS-CoV-2 via high-throughput inverse docking (version 1)

Screening already approved drugs for activity against a novel pathogen can be an important part of global rapid-response strategies in pandemics. Such high-throughput repurposing screens have already identified several existing drugs with potential to combat SARS-CoV-2. However, moving these hits forward for possible development into drugs specifically against this pathogen requires unambiguous identification of their corresponding targets, something the high-throughput screens are not typically designed to reveal. We present here a new computational inverse-docking protocol that uses all-atom protein structures and a combination of docking methods to rank order targets for each of several existing drugs for which a plurality of recent hight-hroughput screens detected anti-SARS-CoV-2 activity. We demonstrate validation of this method with known drug-target pairs, including both non-antiviral and antiviral compounds. We subjected 152 distinct drugs potentially suitable for repurposing to the inverse docking procedure. The most common preferential targets were the human enzymes TMPRSS2 and PIKfyve, followed by the viral enzymes Helicase and PLpro. All compounds that selected TMPRSS2 are known serine protease inhibitors, and those that selected PIKfyve are known tyrosine kinase inhibitors. Detailed structural analysis of the docking poses revealed important insights into why these selections arose, and could potentially lead to more rational design of new drugs against these targets.Fil: Ribone, Sergio P. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Ciencias Farmacéuticas; Argentina.Fil: Ribone, Sergio P. Consejo Nacional de Investigaciones Científicas y Técnicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; Argentina.Fil: Paz; S. Alexis. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas; Argentina.Fil: Paz, S. Alexis. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Físico-química de Córdoba; Argentina.Fil: Abrams, Cameron F. Drexel University. Department of Chemical and Biological Engineering, Philadelphia; United States.Fil: Villarreal Marcos A. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas; Argentina.Fil: Villarreal Marcos A. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Físico-química de Córdoba; Argentina.Fil: Paz; S. Alexis. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas; Argentina

Target identification for repurposed drugs active against SARS-CoV-2 via high-throughput inverse docking

Screening already approved drugs for activity against a novel pathogen can be an important part of global rapid-response strategies in pandemics. Such high-throughput repurposing screens have already identified several existing drugs with potential to combat SARS-CoV-2. However, moving these hits forward for possible development into drugs specifically against this pathogen requires unambiguous identification of their corresponding targets, something the high-throughput screens are not typically designed to reveal. We present here a new computational inverse-docking protocol that uses all-atom protein structures and a combination of docking methods to rank-order targets for each of several existing drugs for which a plurality of recent high-throughput screens detected anti-SARS-CoV-2 activity. We demonstrate validation of this method with known drug-target pairs. We subjected 152 distinct drugs potentially suitable for repurposing to the inverse docking procedure. Detailed structural analysis revealed important insights and could potentially lead to more rational design of new drugs against these targets

Rational Approaches for the Design of Effective Human Immunodeficiency Virus Type 1 Nonnucleoside Reverse Transcriptase Inhibitors

The binding of several classes of nonnucleoside reverse transcriptase inhibitors (NNRTIs) to wild-type (wtRT) and K103N mutant (mRT) human immunodeficiency virus type 1 (HIV-1) reverse transcriptase is studied by molecular dynamics and energy decomposition techniques. The imidoylthiourea (ITU), diaryltriazine (DATA), and diarylpyrimidine (DAPY) NNRTIs studied maintain the hydrogen bond with Lys101 during the 3 ns molecular dynamics trajectories. When bound to mRT, all the DAPYs studied establish hydrogen bonds with Glu138; among these, those of the potent inhibitors TMC120 and TMC125 are water-mediated. The molecular interactions of the NNRTIs in the binding pocket are correlated to the drugs' potency. Quantitative free energy analyses show a linear relationship between the van der Waals energetic component and the potency against wtRT. The molecular basis of the interaction between NNRTIs and RT presented here provide quantitative approaches for the design of novel effective anti-HIV drugs. © 2011 American Chemical Society.Fil: Ribone, Sergio Roman. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; ArgentinaFil: Quevedo, Mario Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Unidad de Investigación y Desarrollo en Tecnología Farmacéutica; ArgentinaFil: Madrid, Marcela. University of Pittsburgh at Johnstown; Estados UnidosFil: Briñon, Margarita Cristina. University of Pittsburgh at Johnstown; Estados Unido