Computer-aided Study On Antiviral Lead Compounds Against Sars-CoV-2

The linear polysaccharide heparan sulfate(HS),which is found in abundance on the cell surface and in the extracellular matrix of most animal tissues,plays various roles in disease development.HS can function as a co-receptor to facilitate the viral spike(S)protein receptor binding domain(RBD)attach to the host cell surface receptor angiotensin-converting enzyme2(ACE2)during the invasion of SARS-CoV-2.In this thesis,HS analogue lead compounds were designed using a computational approach,and novel molecules were produced with potential inhibitory activity for the RBD-HS-ACE2 interaction.The main contents of this paper are as follows:(1)Using various computational techniques,disaccharide lead compounds are designed.We created a database of 96 disaccharide structures that are composed of the three sugar units in HS.Based on the types of amino acid residues implicated in the interaction with HS on the RBD,we have built the pharmacophore models SBP-1 and SBP-2 for the SARS-CoV-2 RBD and the SARS-CoV-2 Omicron BA.1 RBD.Using this model,we discovered the lead disaccharide compounds LBJ-1 and LBJ-2 by virtual screening of the disaccharide database.Second,we have performed molecular docking and intermolecular interaction analysis for the antiviral medications/compounds with experimentally or clinically verified inhibitory effects on SARS-CoV-2.In comparison,LBJ-1 and LBJ-2 both have better binding activities to RBDs and the potential to attenuate inflammatory responses than the antiviral medications/compounds.The interactions of the antiviral medications with RBDs were mostly focused on Trp353,Arg355,Phe464,and Arg466,among which Trp353,Arg355,and Arg466 are amino acid residues at the RBD-HS-ACE2 binding interface,therefore Phe464 may have the potential to be utilized as a target for the development of novel therapies targeting RBD.Additionally,by molecular dynamics(MD)simulations of LBJ-1 and LBJ-2with RBDs,we have discovered that the binding sites of LBJ-1 and LBJ-2 to RBDs were shifted in comparison to molecular docking but still located on the RBD-HS-ACE2 binding interface,further supporting the disaccharide lead compounds’ binding mechanism with RBD.Further,we computed the HOMO-LUMO energy differences LBJ-1 and LBJ-2,to predict druggability and stability,showing that they are chemically stable.The anticipated pharmacokinetic and toxicological features of the two disaccharides also suggest that they have low plasma protein binding(PPB),correct volume distribution(VD),and poor blood-brain barrier(BBB)permeability.(2)As a continuation study,we have created a pentasaccharide database that is composed of 14112 different structures.Based on RBD structures,we then performed a virtual screening of the pentasaccharide database and identified one compound,AD08043 that displayed the highest affinity to RBD.In comparison with reported HS-mimetics that have been demonstrated binding to the SARS-CoV-2 RBD by molecular docking and force analysis.The results revealed that binding sites of to RBD of all compounds were positioned close to the RBD-HS-ACE2 binding interface,satisfying the binding mechanism of amino acid interaction with the RBD-HS-ACE2 binding interface,but AD08043 exhibited superior binding activity to RBD compared to the HS analogues.Further analysis has shown that the locations of the AD08043 binding sites to various SARS-CoV-2 mutant strains(Alpha,Beta,Gama,Delta,Omicron BA.1)RBDs were close to the RBD-HS-ACE2 binding interface,demonstrating that the binding of AD08043 to various mutant strains also satisfied the binding mechanism.MD simulations of the AD08043-SARS-CoV-2 RBD complex discovered that the negatively charged AD08043 was situated on the electropositive surface of the RBD at the majority of time points during the dynamic changes,and the Arg357 has repeatedly occurred in the interaction,therefore may be a crucial amino acid residue to maintain the structural stability of the complex.Analysis of the stability and druggability of the compounds revealed that AD08043 had a higher energy difference than the HS-analogues,indicating stronger chemical stability.Assessment of its pharmacokinetic and toxicological qualities of AD08043 anticipated that it would have lower PPB,appropriate VD,inferior BBB permeability,and lower drug toxicity.In summary,this study has focused on the identification of novel oligosaccharide structures that bind to RBD with high affinity by multiple computational methods.HS-analogue lead compounds with different chain lengths were designed to establish the disaccharides and pentasaccharides databases for virtual screening;the binding affinity and mechanism between lead compounds with target proteins were derived using molecular docking and intermolecular interaction analysis;the dynamic changes of the lead compound-target protein complex were obtained by molecular dynamics(MD)simulation,and the binding mechanism was further validated by the results;the lead compounds’ chemical stability and drug-likeness were determined by quantum chemical analysis and ADMET prediction;the generation of novel compounds with a high theoretical potential to become anti-SARS-CoV-2 chemicals.The results in this thesis can provide important information in the development of medications for the treatment of COVID-19.