Design of Novel Enantiopure Dispirooxindolopyrrolidine-Piperidones as Promising Candidates toward COVID-19: Asymmetric Synthesis, Crystal Structure and In Silico Studies

Abstract

Despite the effectiveness of COVID-19 vaccines, there is still an urgent need for discovering new anti-viral drugs to address the awful spread and transmission of the rapidly modifiable virus. In this study, the ability of a small library of enantiomerically pure spirooxindolopyrrolidine-grafted piperidones to inhibit the main protease of SARS-CoV-2 (Mpro) is evaluated. These spiroheterocycles were synthesized by 1,3-dipolar cycloaddition of various stabilized azomethine ylides with chiral dipolarophiles derived from N-[(S)-(-)-methylbenzyl]-4-piperidone. The absolute configuration of contiguous carbons was confirmed by a single crystal X-ray diffraction analysis. The binding of these compounds to SARS-CoV-2 Mpro was investigated using molecular docking and molecular dynamics simulation. Three compounds 4a, 4b and 4e exhibited stable binding modes interacting with the key subsites of the substrate-binding pocket of SARS-CoV-2 Mpro. The synthesized compounds represent potential leads for the development of novel inhibitors of SARS-CoV-2 main protease protein for COVID-19 treatment.

Virtual Screening and Biological Evaluation of Potential PD-1/PD-L1 Immune Checkpoint Inhibitors as Anti-Hepatocellular Carcinoma Agents

“…For the complexes of PDL-1 with each of compound H1 , H4 , and H6 , MD simulations were carried out using the PMEMD.cuda code of the AMBER Molecular Dynamics package following the same previously described protocol of minimization, heating, density equilibration, and production. , The trajectory lengths for heating, density equilibration, and production were 20 ps, 200 ps, and 100 ns, respectively. The trajectories were analyzed using CPPTraj .…”