COVID-19 pandemic has killed millions of people
worldwide since its outbreak in Dec 2019. The pandemic is caused by the SARS-CoV-2
virus whose main protease (Mpro) is a promising drug target since it plays a
key role in viral proliferation and replication. Currently, designing an
effective therapy is an urgent task, which requires accurately estimating ligand-binding
free energy to the SARS-CoV-2 Mpro. However, it should be noted that the
accuracy of a free energy method probably depends on the protein target. A
highly accurate approach for some targets may fail to produce a reasonable
correlation with experiment when a novel enzyme is considered as a drug target.
Therefore, in this context, the ligand-binding affinity to SARS-CoV-2 Mpro was
calculated via various approaches. The Autodock Vina (Vina) and Autodock4 (AD4)
packages were manipulated to preliminary investigate the ligand-binding
affinity and pose to the SARS-CoV-2 Mpro. The binding free energy was then refined
using the fast pulling of ligand (FPL), linear interaction energy (LIE),
molecular mechanics-Poission Boltzmann surface
area (MM-PBSA), and free energy perturbation (FEP) methods. The benchmark
results indicated that for docking calculations, Vina is more accurate than AD4
and for free energy methods, FEP is the
most accurate followed by LIE, FPL and MM-PBSA (FEP > LIE > FPL >
MM-PBSA). Moreover, the binding mechanism was also revealed by atomistic
simulations. The vdW interaction is the dominant factor. The residues <i>Thr25</i>,
<i>Thr26</i>, <i>His41</i>, <i>Ser46</i>, <i>Asn142</i>, <i>Gly143</i>, <i>Cys145</i>,
<i>Glu166</i>, and <i>Gln189</i> are essential elements affecting on the
binding process. Furthermore, the <i>Ser46</i>
and related residues probably are important elements affecting the enlarge/dwindle
of the SARS-CoV-2 Mpro binding cleft. The benchmark probably guide for further
investigations using computational approaches.
Alchemical Absolute Protein-Ligand Binding Free Energies for Drug Design
