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Computer-Aided Approaches to De Novo Design of drug candidates targeting the SARS-CoV-2 Spike protein bound to angiotensin converting enzyme 2 (ACE2)
preprintsubmitted on 18.03.2021, 20:37 and posted on 24.03.2021, 04:49 by Konstantinos Kalamatianos
In this study a computer-aided approach to de novo design of chemical entities with drug-like properties against the SARS-CoV-2 Spike protein bound to ACE2 is presented. A structure-based de novo drug design tool LIGANN was used to produce complementary ligand shapes to the SARS-CoV-2 Spike protein (6M0J). The obtained ligand structures - potential drug candidates – were optimized and virtually screened. Hit ligands were considered all that showed initial binding energy scores ≤ -9.0 kcal.mol-1 for the protein. These compounds were tested for drug-likeness (Lipinski’s rule and BOILED Permeation Predictive Model). All satisfying the criteria were re-optimized (geometry & frequencies) at the HF-3c33 level of theory and virtually screened against 6M0J. Molecular dynamics (MD) simulations were used to assess the structural stability of selected 6M0J/novel compound complexes. Synthetic pathways for selected compounds from commercially available starting materials are proposed.