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Computational Biology and Bioinformatics in Anti-SARS-CoV-2 Drug Development
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Based on the presumption that the extremely highly conserved regions of SARS-CoV-2 proteins (i.e., regions recognizable across many viruses and organisms) may serve as important targets, being related to crucial functions and less likely to exhibit escape mutations that would make them resistant to vaccines and therapeutic agents, Robson et al. conducted a comprehensive search for such regions in all open reading frames of SARS-CoV-2 [98]. This analysis revealed the presence of such an extremely highly conserved motif in the SARS-CoV-2 NSP3. This motif is related to the highly conserved structural module known as the macro domain, which is broadly distributed across various organisms, including humans [98]. The authors also pointed to the presence of three especially conserved subsequences, VVVNAANVYLKHGGGVAGALNK, PLLSAGIFG, and LHVVGPNVNKG, in NSP3 [98].
Chikungunya Virus Infection
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
D. Velmurugan, K. Manish, D. Gayathri
Helene et al. (2009) determined the crystal structures of CHIKV-nsP3 and VEEV-nsP3 macrodomains. These domains are found to be active as adenosine di-phosphoribose-1’’-phosphate phosphatases. Both these macrodomains are ADP-ribose binding modules, as revealed by structural and functional analysis. A single aspartic acid was found to be conserved through all macrodomains, responsible for the specific binding of the adenine base. The crystal structure of CHIKV-nsP3 protease macrodomain with an RNA trimer reveals the binding mode that utilizes the same adenine-binding pocket as ADP-ribose but avoids the ADP-ribose 1’’-phosphate phosphatase active site. Authors have concluded that the CHIKV macrodomain has a specificity for (i) an adenine rather than a guanine (ii) two phosphate groups rather than either one or three and (iii) a ribose at the distal position. Although CHIKV and VEEV macrodomains bind ADP-ribose, they exhibit a quite different thermal denaturation shift profile. CHIKV macrodomain was found to lose its stability to bind ADP-ribose when the D10 position was changed to alanine.
Hepatitis E Virus
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
Kavita Lole, Prudhvi Lal Bhukya, Bangari Haldipur
HVR and PRR domains lie between the PCP domain and macro domain. These domains vary in length and sequence across different strains of HEV.54 It is suggested that HVR may influence efficiency of HEV replication, possibly via its interaction with viral or host factors or both.55
Analysis of the SARS-CoV-2-host protein interaction network reveals new biology and drug candidates: focus on the spike surface glycoprotein and RNA polymerase
Published in Expert Opinion on Drug Discovery, 2021
Esen Sokullu, Maxime Pinard, Marie-Soleil Gauthier, Benoit Coulombe
Upon host cell infection by SARS-CoV-2, replication and transcription of the viral genome made of a single-stranded RNA (ssRNA) molecule is carried out by a multiprotein complex composed of non-structural viral proteins (NSP) (Figure 4). This replication and transcription complex (RTC) is composed of eight NSPs: NSP7-10, NSP12-14 and NSP16; all of which being required for efficient in vivo viral propagation as shown for other nidoviruses [71–74]. These SARS-CoV-2 NSPs are highly similar to their SARS-CoV equivalents (93.29% to 100% homology) [75] and are expressed from the cleavage of two polyproteins translated by the host ribosomes from the 5ʹ portion of the viral genome [76]. Their maturation is carried out by the two viral proteases NSP3 (papain-like proteinase) and NSP5 (3-chymotrypsin-like proteinase) [77,78] that are also promising target for drug development and existing marine natural compounds [79]. Moreover SARS-CoV-2 NSP3 macrodomain was shown to have a stronger interaction with ADP-ribose by docking experiment suggesting also a role in the host antiviral response [8]. Other non-structural proteins are also important in the replication of the viral genome. The nucleocapsid (N) was also shown to be required in viral RNA synthesis of betacoronavirus [80] and SARS-CoV-2 N protein interaction with RNA has been assessed [81].
An overview of Middle East respiratory syndrome coronavirus vaccines in preclinical studies
Published in Expert Review of Vaccines, 2020
Naru Zhang, Jian Shang, Chaoqun Li, Kehui Zhou, Lanying Du
The structure and/or function of several non-structural proteins (nsps) of MERS-CoVs have been identified [48]. For example, the nsp3 protein contains a conserved macro domain that binds efficiently to adenosine diphosphate (ADP)-ribose [58]. Nsp13 is a helicase with multiple domains [59]. Nsp15 is an endoribonuclease with high affinity for the nsp7/8 complex [60]. Nsp16 is needed for interferon resistance and viral pathogenesis [61]. The crystal structures of MERS-CoV nsp3 macro protein complexed with ADP-ribose, as well as MERS-CoV nsp13 and nsp15 proteins, have been identified [58–60] (Figure 5), providing valuable information and increasing our understanding of the function of these proteins. Generally, the accessory proteins of MERS-CoV antagonize host antiviral responses and are important for helping the virus evade host innate immune responses [55,62], among which ORF 3 to ORF 5 are associated with virulence [63].
In silico docking studies and synthesis of new phosphoramidate derivatives of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole as potential antimicrobial agents
Published in Journal of Receptors and Signal Transduction, 2020
Munichandra Reddy Sivala, Venkataramaiah Chintha, Krishna Murthy Potla, Sampath Chinnam, Naga Raju Chamarthi
The three-dimensional structure of Human Poly (ADP ribose) Polymerase 15 (ARTD7, BAL3) Macro domain (PDB: 3V2B) and the reference compounds, such as norfloxacin and nystatin, were downloaded from the RCSB protein data bank. The atomic coordinates of the protein was estranged and geometry optimization was performed using Argus Lab 4.0.1. The enzyme 3V2B, and the reference drugs are shown in Figure 2. The chemical structures of compounds were prepared using Chem Biodraw and converted all the ligands into Pdbqt file format and atomic coordinates were generated using Pyrx 2010.12.