Computer-Aided Approaches to De Novo Design of drug candidates targeting the SARS-CoV-2 Spike protein bound to angiotensin converting enzyme 2 (ACE2)

24 March 2021, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


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.


drug design
computer assisted design
SARS-CoV-2 Spike protein
virtual screening
In silico screening
Molecular docking computations
computatinal drug screening
Molecular Dynamic Simulations
novel inhibitors
de novo design


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