Protein degradation: a novel computational approach to design protein degrader probes for main protease of SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has afflicted many lives and led to approvals of drugs and vaccines for emergency use. Even though vaccines have emerged, the high mortality of COVID-19 and its insurgent proliferation throughout the masses commands an innovative therapeutic proposition for the treatment. Targeted protein degradation has been applied to various disease domains and we propose that it could be incredibly beneficial to tackle the current pandemic. In this study, we have attempted to furnish insights on the design of suitable PROTACs for the main protease (Mpro) of SARS-CoV-2, a protein that is considered to be an essential target for viral replication. We have employed protein-protein docking to predict the possible complementarity between a cereblon E3 ligase and Mpro of SARS-CoV-2, and estimate possible linker length. Molecular Dynamic simulation and analysis on generated ternary complexes demonstrated stable interactions that suggested that designed PROTAC has a potential to cause degradation. The superior characteristics rendered by PROTACS led us to propose them as possibly the next-generation antiviral drugs for SARS-CoV-2.

Identification of prospective covalent inhibitors for SARS-CoV-2 main protease using structure-based approach.

The rapid global spread of SARS-CoV-2 has recently caused havoc and forced the world into a state of the pandemic causing respiratory, gastrointestinal, hepatic, and neurologic diseases. It persistently, through mutation, develops into new variants of the virus that have appeared over time. As main protease (Mpro) is involved in proteolysis of two overlapping polyproteins pp1a and pp1ab to produce 16 non-structural proteins having a paramount factor in the virus replication that have a cysteine-histidine catalytic dyad. A computational approach, guiding a covalent docking as it offers higher potency, long duration of action and decreased drug resistance advantages over the conventional docking of the ligands on a catalytic dyad, is applied for SARS-CoV-2 main protease (Mpro) in this manuscript to divulge better molecules. Mpro active site contains Cys145 residue which act as a nucleophile and can donate its electron to an electrophilic molecule by interacting covalently. Furthermore, the ligand-protein complexes are allowed to simulate their dynamic studies to look into their time-based interaction stability and also, a parallel study of ADME properties for the hit molecules is also performed. Important insights from the studies revealed that the interactions are persistent and molecules may be considered for further optimization in clinical investigation.Communicated by Ramaswamy H. Sarma.

Identification of Potential ACE2-Derived Peptide Mimetics in SARS-CoV-2 Omicron Variant Therapeutics using Computational Approaches.

The COVID-19 pandemic has become a global health challenge because of the emergence of distinct variants. Omicron, a new variant, is recognized as a variant of concern (VOC) by the World Health Organization (WHO) because of its higher mutations and accelerated human infection. The infection rate is strongly dependent on the binding rate of the receptor binding domain (RBD) against human angiotensin converting enzyme-2 (ACE2human) receptor. Inhibition of protein-protein (RBDs(SARS-CoV-2/omicron)-ACE2human) interaction has been already proven to inhibit viral infection. We have systematically designed ACE2human-derived peptides and peptide mimetics that have high binding affinity toward RBDomicron. Our peptide mutational analysis indicated the influence of canonical amino acids on the peptide binding process. Herein, efforts have been made to explore the atomistic details and events of RBDs(SARS-CoV-2/omicron)-ACE2human interactions by using molecular dynamics simulation. Our studies pave a path for developing therapeutic peptidomimetics against omicron.

Rapid structure-based identification of potential SARS-CoV-2 main protease inhibitors.

The COVID-19 outbreak has thrown the world into an unprecedented crisis. It has posed a challenge to scientists around the globe who are working tirelessly to combat this pandemic. We herein report a set of molecules that may serve as possible inhibitors of the SARS-CoV-2 main protease. To identify these molecules, we followed a combinatorial structure-based strategy, which includes high-throughput virtual screening, molecular docking and WaterMap calculations. The study was carried out using Protein Data Bank structures 5R82 and 6Y2G. DrugBank, Enamine, Natural product and Specs databases, along with a few known antiviral drugs, were used for the screening. WaterMap analysis aided in the recognition of high-potential molecules that can efficiently displace binding-site waters. This study may help the discovery and development of antiviral drugs against SARS-CoV-2.

Identification of potential SARS-CoV-2 Mpro inhibitors integrating molecular docking and water thermodynamics.

The COVID-19 pandemic is an ongoing global health emergency caused by a newly discovered coronavirus SARS-CoV-2. The entire scientific community across the globe is working diligently to tackle this unprecedented challenge. In silico studies have played a crucial role in the current situation by expediting the process of identification of novel potential chemotypes targeting the viral receptors. In this study, we have made efforts to identify molecules that can potentially inhibit the SARS-CoV-2 main protease (Mpro) using the high-resolution crystal structure of SARS-CoV-2 Mpro. The SARS-CoV-2 Mpro has a large flexible binding pocket that can accommodate various chemically diverse ligands but a complete occupation of the binding cavity is necessary for efficient inhibition and stability. We augmented glide three-tier molecular docking protocol with water thermodynamics to screen molecules obtained from three different compound libraries. The diverse hits obtained through docking studies were scored against generated WaterMap to enrich the quality of results. Five molecules were selected from each compound library on the basis of scores and protein-ligand complementarity. Further MD simulations on the proposed molecules affirm the stability of these molecules in the complex. MM-GBSA results and intermolecular hydrogen bond analysis also confirm the thermodynamic stability of proposed molecules. This study also presumably steers the structure determination of many ligand-main protease complexes using x-ray diffraction methods.Communicated by Ramaswamy H. Sarma.