The advent of multiple rigorous molecular simulation approaches made it possible to unveil molecular mechanisms on atomic level and capture the dynamic features of biomolecules. In this thesis, we will introduce three research projects accomplished using molecular simulations to facilitate drug discovery. Firstly, the COVID-19 pandemic caused by SARS-CoV-2 has resulted in half a billion infections worldwide and effective antivirals are required to curb the pandemic. Nucleotide analogs inhibiting RNA-dependent RNA polymerase (RdRp) represents a well-established strategy to inhibit virus amplification although the inhibitory mechanism was not fully understood. To explain the impact of 2’-modification on inhibition activity against SARS-CoV-2 RdRp, extensive molecular dynamics (MD) simulat...[ Read more ]

The advent of multiple rigorous molecular simulation approaches made it possible to unveil molecular mechanisms on atomic level and capture the dynamic features of biomolecules. In this thesis, we will introduce three research projects accomplished using molecular simulations to facilitate drug discovery. Firstly, the COVID-19 pandemic caused by SARS-CoV-2 has resulted in half a billion infections worldwide and effective antivirals are required to curb the pandemic. Nucleotide analogs inhibiting RNA-dependent RNA polymerase (RdRp) represents a well-established strategy to inhibit virus amplification although the inhibitory mechanism was not fully understood. To explain the impact of 2’-modification on inhibition activity against SARS-CoV-2 RdRp, extensive molecular dynamics (MD) simulations and free energy perturbation (FEP) were conducted. We found that small-size modifications such as fluorine had little impact on RNA replication. By contrast, 2’- methyl modification led to immediate RNA chain termination due to intermolecular steric clash, while the instability at 3’-terminal caused by 2’-methyl substitution resulted in partial termination. Secondly, incorporation of two consecutive Favipiravir was found to inhibit RNA replication mediated by influenza A virus RdRp. Yet the detailed mechanism remains elusive. We performed MD simulations and unveiled that the disrupted active site was a consequence of the altered base stacking pattern. The first two projects provide valuable insights into the structural optimization of antivirals on atomic level. Thirdly, cerebral cavernous malformations (CCM) patients have limited options on safe and effective treatments. A recent study discovered the strong association between type II CCM and the somatic mutation of MAP3K3 gene encoding a protein kinase MEKK3. The overactive MEKK3 I441M variant provides a promising target for the type II CCM therapy. Accordingly, we performed a series of molecular docking to repurpose approved/investigational kinase inhibitors for MEKK3 I441M variant inhibition. 14 potential type 1.5 inhibitors with selectivity were recommended for further activity verification.