Inhibition Mechanism of Anti-TB Drug SQ109: Allosteric Inhibition of TMM Translocation of Mycobacterium Tuberculosis MmpL3 Transporter.

The mycolic acid transporter MmpL3 is driven by proton motive forces (PMF) and functions via an antiport mechanism. Although the crystal structures of the MmpL3 transporter alone and in complex with a trehalose monomycolate (TMM) substrate and an antituberculosis drug candidate SQ109 under Phase 2b-3 Clinical Trials are available, no water and no conformational change in MmpL3 were observed in these structures to explain SQ109's inhibition mechanism of proton and TMM transportation. In this study, molecular dynamics simulations of both apo form and inhibitor-bound MmpL3 in an explicit membrane were used to decipher the inhibition mechanism of SQ109.

Novel inhibitors to ADP ribose phosphatase of SARS-CoV-2 identified by structure-based high throughput virtual screening and molecular dynamics simulations.

The outbreak of a new coronavirus (SARS-CoV-2) was first identified in Wuhan, People's Republic of China, in 2019, which has led to a severe, life-threatening form of pneumonia (COVID-19). Research scientists all around the world have been trying to find small molecule drugs to treat COVID-19. In the present study, a conserved macrodomain, ADP Ribose phosphatase (ADRP), of a critical non-structural protein (Nsp3) in all coronaviruses was probed using large-scale Molecular Dynamics (MD) simulations to identify novel inhibitors.