PMC:5056895 / 1755-7394 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/5056895","sourcedb":"PMC","sourceid":"5056895","source_url":"https://www.ncbi.nlm.nih.gov/pmc/5056895","text":"Introduction\nZika virus (ZIKV), belongs to family \"Flaviviradae\" having genus \"Flavivirus\" [1], is a mosquito-borne flavivirus. It transmits mainly through vectors from the Aedes genus and monkeys [2]. Humans get infected by infected mosquito bites or by direct contact probably during sexual intercourse [3]. Symptoms associated with the viral infection are fever, mild headache, malaise, conjunctivitis, rashes, and arthralgia. The illness by ZIKV is usually not much severe and there is a long-term symptoms for more than a few days to a week after infected by mosquito. As the mortality rate of ZIKV infection is very rare with less severe sickness, many people might not realize they have been infected. There is an augmented risk of microcephaly development along with severe fetal brain defects in the fetus of pregnant women when she infected with ZIKV [4]. In 1947, the ZIKV was first isolated from the blood of a sentinel rhesus monkey number 766 living in Zika forest at Uganda [2]. In 2007, ZIKV spreads from Africa and Asia to cause the largest outbreak in humans on Pacific island of Yap [5]. There are around 73% of yep residents over the age of 3 years were infected with ZIKV whereas no deaths were subjected [56].\nThe viral illness become apparent disease due to the increasing distribution area of ZIKV, confirming by the recent epidemic French Polynesia, new Caledonian since October 2013 [7] and crook island in March 2014. In May 2015, the Pan American Health Organization and World Health Organization (WHO) issued an epidemiological alert to ZIKV infection [8]. Brazilian health officials confirm a case of ZIKV infection transmitted by transfused blood from an infected donor in February 2016. There are two types of diagnosis for ZIKV are available, one is the detection of the virus and viral components through reverse transcription polymerase chain reaction, immunoassay and virus isolation and the other one is based on the antibody detection extracted by ZIKV infection [6]. A preliminary diagnosis is also carried out based on patients clinical features, place and date of travel and activities. Laboratory diagnosis is generally able by testing serum or plasma to detect virus.\nZIKV consist of a single stranded, positive sense, 5'-capped RNA with genome size of around 11 kb which immediately released into the cytoplasm following by cell entry [9]. There are 59 and 39 un-translated regions along with only one open reading frame which codes a polyprotein that further cleaved into three structural proteins i.e., the capsid (c), envelope (E) and premembrane/membrane (prM); and seven nonstructural (NS) proteins i.e., NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5 [10]. Among them the NS3 and NS5 proteins play a central role, together they harbor most of the catalytic activities needed for capping and replication [9]. The NS5 consist of an N-terminal methyl-transferase (NS5 MTase) domain, c-terminal RNA dependent, RNA polymerase (NS5 RdRp). Whereas NS3 is a multi-domain protein with an N-terminal NS3pro and c-terminal fraction containing the RNA triphosphatase (NS3 RTpase) and RNA helicase (NS3 hel) activities involves in viral RNA synthesis [111213]. The 375 kDa flaviviral polyprotein precursor is processed by host proteases and a virus encoded protease activity localized at the N-terminal domain of NS3. Whereas at the junctions prM-E, C-prM, NS4A-NS4B, E-NS1 [1415], and likely also NS1-NS2A [16], is carried out by the host signal peptidase located within the lumen of endoplasmic reticulum, the left over peptide bonds between NS2B-NS3, NS2A-NS2B, NS3-NS4A, and NS4B-NS5 are cleaved by NS3Pro. Cleavage at the NS2B/NS3 site is carried out in cis but is not essential for protease activity [1718]. Thus, the protease activity of NS3 protein is very essential for viral replication and its inhibition has to be evaluated as a valuable approach for treatment against flaviviral infections [9]. Thus, the NS3 protein may be considered as important drug target. Currently, there is no medicines and vaccines developed against ZIKV or specific antiviral treatment for clinical ZIKV infection. Treatment is normally supportive and can include rest, intake of fluids, and use of antipyretics and analgesics [19].\nThere are some Food and Drug Administration (FDA) approved drugs such as: amodiaquine [20], prochlorperazine [21], quinacrine, and berberine [22], were reported to be effective (in vitro or in vivo) against dengue virus (DENV) which is also a Flavivirus. There are many things that dengue and Zika have in common like they both are mosquito borne viruses spread especially by the Aedes mosquito. Both have similar symptoms. The difference is that ZIKV symptoms last for few days or weeks and then they subside but for dengue the fever last for weeks and that can further lead to bruising and bleeding. Both dengue and Zika have three structural proteins and seven nonstructural. Quinacrine is also active against Ebola virus [23]. As ZIKV also belong to the Flaviviradae family, these drugs may have some therapeutic effect against ZIKV. Thus in this study, we have taken these four FDA approved drugs against DENV as ligands and performed molecular docking analysis against NS3 protein of ZIKV in order to observe the binding affinity of these drugs. Among these four drugs, the drug showing minimum binding energy has been considered as the lead drug for further analysis. Further, drug like compounds with similar physiochemical properties of the lead drug, have been retrieved from ZINC database for virtual screening against NS3 protein, in order to identify novel drugs for ZIKV.","divisions":[{"label":"Title","span":{"begin":0,"end":12}}],"tracks":[{"project":"2_test","denotations":[{"id":"27729840-19788800-44841829","span":{"begin":198,"end":199},"obj":"19788800"},{"id":"27729840-21529401-44841830","span":{"begin":306,"end":307},"obj":"21529401"},{"id":"27729840-26820244-44841831","span":{"begin":862,"end":863},"obj":"26820244"},{"id":"27729840-19788800-44841832","span":{"begin":990,"end":991},"obj":"19788800"},{"id":"27729840-19516034-44841833","span":{"begin":1103,"end":1104},"obj":"19516034"},{"id":"27729840-19516034-44841834","span":{"begin":1227,"end":1228},"obj":"19516034"},{"id":"27729840-18680646-44841835","span":{"begin":1227,"end":1229},"obj":"18680646"},{"id":"27729840-14230895-44841836","span":{"begin":1410,"end":1411},"obj":"14230895"},{"id":"27729840-18680646-44841837","span":{"begin":2002,"end":2003},"obj":"18680646"},{"id":"27729840-19945487-44841838","span":{"begin":2380,"end":2381},"obj":"19945487"},{"id":"27729840-24903869-44841839","span":{"begin":2697,"end":2699},"obj":"24903869"},{"id":"27729840-19945487-44841840","span":{"begin":2849,"end":2850},"obj":"19945487"},{"id":"27729840-11050942-44841841","span":{"begin":3184,"end":3186},"obj":"11050942"},{"id":"27729840-12032088-44841842","span":{"begin":3184,"end":3188},"obj":"12032088"},{"id":"27729840-16912287-44841843","span":{"begin":3184,"end":3190},"obj":"16912287"},{"id":"27729840-2826667-44841844","span":{"begin":3407,"end":3409},"obj":"2826667"},{"id":"27729840-2705302-44841845","span":{"begin":3407,"end":3411},"obj":"2705302"},{"id":"27729840-7474145-44841846","span":{"begin":3440,"end":3442},"obj":"7474145"},{"id":"27729840-11581268-44841847","span":{"begin":3739,"end":3741},"obj":"11581268"},{"id":"27729840-17337448-44841848","span":{"begin":3739,"end":3743},"obj":"17337448"},{"id":"27729840-19945487-44841849","span":{"begin":3936,"end":3937},"obj":"19945487"},{"id":"27729840-24680954-44841850","span":{"begin":4341,"end":4343},"obj":"24680954"},{"id":"27729840-25028694-44841851","span":{"begin":4364,"end":4366},"obj":"25028694"},{"id":"27729840-20973722-44841852","span":{"begin":4396,"end":4398},"obj":"20973722"},{"id":"27729840-26834994-44841853","span":{"begin":4980,"end":4982},"obj":"26834994"}],"attributes":[{"subj":"27729840-19788800-44841829","pred":"source","obj":"2_test"},{"subj":"27729840-21529401-44841830","pred":"source","obj":"2_test"},{"subj":"27729840-26820244-44841831","pred":"source","obj":"2_test"},{"subj":"27729840-19788800-44841832","pred":"source","obj":"2_test"},{"subj":"27729840-19516034-44841833","pred":"source","obj":"2_test"},{"subj":"27729840-19516034-44841834","pred":"source","obj":"2_test"},{"subj":"27729840-18680646-44841835","pred":"source","obj":"2_test"},{"subj":"27729840-14230895-44841836","pred":"source","obj":"2_test"},{"subj":"27729840-18680646-44841837","pred":"source","obj":"2_test"},{"subj":"27729840-19945487-44841838","pred":"source","obj":"2_test"},{"subj":"27729840-24903869-44841839","pred":"source","obj":"2_test"},{"subj":"27729840-19945487-44841840","pred":"source","obj":"2_test"},{"subj":"27729840-11050942-44841841","pred":"source","obj":"2_test"},{"subj":"27729840-12032088-44841842","pred":"source","obj":"2_test"},{"subj":"27729840-16912287-44841843","pred":"source","obj":"2_test"},{"subj":"27729840-2826667-44841844","pred":"source","obj":"2_test"},{"subj":"27729840-2705302-44841845","pred":"source","obj":"2_test"},{"subj":"27729840-7474145-44841846","pred":"source","obj":"2_test"},{"subj":"27729840-11581268-44841847","pred":"source","obj":"2_test"},{"subj":"27729840-17337448-44841848","pred":"source","obj":"2_test"},{"subj":"27729840-19945487-44841849","pred":"source","obj":"2_test"},{"subj":"27729840-24680954-44841850","pred":"source","obj":"2_test"},{"subj":"27729840-25028694-44841851","pred":"source","obj":"2_test"},{"subj":"27729840-20973722-44841852","pred":"source","obj":"2_test"},{"subj":"27729840-26834994-44841853","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#be93ec","default":true}]}]}}