Putative structural rearrangements associated with the interaction of macrocyclic inhibitors with norovirus 3CL protease

Kankanamalage, Anushka C. Galasiti; Weerawarna, Pathum M.; Rathnayake, Athri D.; Kim, Yun-Jeong; Mehzabeen, N.; Battaile, K.P.; Lovell, Scott; Chang, Kyeong‐Ok; Groutas, William C.

doi:10.1002/prot.25682

Cited by 9 publications

(10 citation statements)

References 52 publications

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“…NV 3CLpro invariably shows a stronger preference for a P 2 Cha versus a P 2 Leu; , however, compounds 5h – 6h display comparatively lower potency. In this instance, gem -dimethyl substitution is inimical to both potency and permeability, possibly arising from subtle conformational effects . Diminished potency was also observed with gem -dimethyl substituted compounds one carbon shorter (Table ), suggesting that the conformational constraints imposed by the gem -dimethyl substitution impact binding adversely.…”

Section: Resultssupporting

confidence: 76%

Structure-Guided Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease

et al. 2020

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Acute gastroenteritis caused by noroviruses has a major impact on public health worldwide in terms of morbidity, mortality, and economic burden. The disease impacts most severely immunocompromised patients, the elderly, and children. The current lack of approved vaccines and small-molecule therapeutics for the treatment and prophylaxis of norovirus infections underscores the need for the development of norovirus-specific drugs. The studies described herein entail the use of the gem-dimethyl moiety as a means of improving the pharmacological activity and physicochemical properties of a dipeptidyl series of transition state inhibitors of norovirus 3CL protease, an enzyme essential for viral replication. Several compounds were found to be potent inhibitors of the enzyme in biochemical and cell-based assays. The pharmacological activity and cellular permeability of the inhibitors were found to be sensitive to the location of the gem-dimethyl group.

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Section: Resultssupporting

confidence: 76%

Structure-Guided Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease

et al. 2020

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“…In general, inhibitors with the aldehyde warhead and Leu or a cyclohexylalanine at the P2 position exhibited decent inhibitory activities. The binding of the macrocyclic inhibitors was facilitated by the hydrogen bonds that also existed in the substrate binding, including the ones between the inhibitor backbone and Gln110, Ala158, Ala160, the ones between the P1 glutamic acid sidechain and Thr134, and His157 [97] (Figure 5D).…”

Section: Macrocyclic Inhibitorsmentioning

confidence: 99%

Norovirus Protease Structure and Antivirals Development

Zhao

Song

et al. 2021

Viruses

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Human norovirus (HuNoV) infection is a global health and economic burden. Currently, there are no licensed HuNoV vaccines or antiviral drugs available. The protease encoded by the HuNoV genome plays a critical role in virus replication by cleaving the polyprotein and is an excellent target for developing small-molecule inhibitors. The current strategy for developing HuNoV protease inhibitors is by targeting the enzyme’s active site and designing inhibitors that bind to the substrate-binding pockets located near the active site. However, subtle differential conformational flexibility in response to the different substrates in the polyprotein and structural differences in the active site and substrate-binding pockets across different genogroups, hamper the development of effective broad-spectrum inhibitors. A comparative analysis of the available HuNoV protease structures may provide valuable insight for identifying novel strategies for the design and development of such inhibitors. The goal of this review is to provide such analysis together with an overview of the current status of the design and development of HuNoV protease inhibitors.

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“…The MM-GBSA interaction energies revealed some important key hotspot amino acid residues for all these drugs. Among these hotspot residues, His41 was conserved among several viruses, including SARS-CoV-2 3CL pro (PDB: 6LU7) [143], SARS-CoV 3CL pro (PDB: 3TNT) [37], and MERS-CoV 3CL pro (PDB: 5WKK) [189] and HCV (PDB: 3M5L) [190].…”

Section: Molecular Modeling Conducted On Sars-cov-2 M Pro / 3cl Promentioning

confidence: 99%

“…By using AutoDock 4.2 software, Gurung and co-workers [191] performed a molecular docking study of some antiviral phytochemicals to identify effective SARS-CoV-2 M pro inhibitors. The sequence analysis revealed that the SARS-CoV-2 3CL pro (PDB: 6LU7) [143] showed 96.08% and 50.65% structural similarity with SARS-CoV 3CL pro (PDB: 3TNT) [37] and MERS-CoV 3CL pro [189]. The superimposition also displayed that SARS-CoV-2 3CL pro had a minute variation with SARS-CoV 3CL pro (RMSD ¼ 0.517 Å ) and MERS-CoV 3CL pro (RMSD ¼ 0.817 Å ).…”

Section: Molecular Modeling Conducted On Sars-cov-2 M Pro / 3cl Promentioning

confidence: 99%

Dissecting the Drug Development Strategies Against SARS-CoV-2 Through Diverse Computational Modeling Techniques

Adhikari

Amin

Jha

2020

Methods in Pharmacology and Toxicology

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The world of the twenty-first century has not experienced such a lockdown situation before, which leads to a complete shutdown of economy not until the novel coronavirus disease 2019 (COVID-19) came caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It becomes an unacceptable global threat to human lives. The COVID-19 has been known only worldwide in the last few months, but it is spreading in a speed of light from Wuhan, China, to the rest of the world. About 2 crore of people have been infected and more than 7 lakh of people have died worldwide till now due to the deadly SARS-CoV-2 infection. There are still no drugs exclusively available in the market for the treatment of SARS-CoV-2 infection, though supportive treatment of hydroxychloroquine, ribavirin, favipiravir, and remdesivir have shown clinical evidences to treat COVID-19. Therefore, it is utmost importance for the medicinal chemists to design and discover novel drugs urgently to rescue or to protect the humanity worldwide from this deadly virus. However, lack of experimental evidences and understanding the behavior of the SARS-CoV-2 within this short period may hinder the process of drug discovery. Still a ray of hope resides in the structural features of SARS-CoV-2 and related coronaviruses (SARS-CoV and MERS-CoV) as these are homologous. Therefore, depending on the established viral target proteins (spike protein, ACE-2, 3CL pro , PL pro , RdRp, helicase, as well as other viral proteins), novel chemical entities may be designed. In this context, several computational modeling approaches (generally structure-based modeling techniques) may be utilized which are cost-effective and less time-consuming. Different structure-based modeling techniques, namely, homology modeling, robust molecular docking, molecular dynamics simulation, and structure-based pharmacophore mapping followed by in silico virtual screening, may be effective and fruitful approaches to design compounds against SARS-CoV-2. In this chapter, various structure-based drug design and discovery strategies from target identification that could be optimized against SARS-CoV-2 have been discussed in detail. Additionally, ongoing and previously reported computational modeling techniques performed by different groups of researchers on various SARS-CoV-2 target proteins have been highlighted elaborately. In addition to the identification techniques of drugs, this chapter also discloses their binding mode of action along with the pharmacokinetics and toxicity criteria computed by modeling techniques. This chapter, therefore, may be a stepping-stone for the researchers to open up a new horizon in the discovery of novel anti-coronavirus drugs in the future.

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Putative structural rearrangements associated with the interaction of macrocyclic inhibitors with norovirus 3CL protease

Cited by 9 publications

References 52 publications

Structure-Guided Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease

Structure-Guided Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease

Norovirus Protease Structure and Antivirals Development

Dissecting the Drug Development Strategies Against SARS-CoV-2 Through Diverse Computational Modeling Techniques

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