The therapeutic indication of all the molecules was identified through DrugBank and DrugCentral databases and the data was analysed to find the therapeutic indications which can be repurposed against 24 SARS-CoV2 targets. The overall distribution of therapeutic indications of top 10 and bottom 10 drugs across the 24 SARS-CoV2 targets are shown in Fig. 6. From the graph it can be observed that the drugs with high binding energy were found to have therapeutic indications for CNS (central nervous system), immunology, cardiology, infectious diseases and pain management. Whereas, the drugs with low binding energy were found to have therapeutic indications for immunology, vitamin deficiency, CNS, infectious disease and anaesthesiology.
[Fig. 6]
Further, the 24 proteins were categorised into five categories based on their role involved in viral biological process viz., cell cycle (Spike, Envelope, Membrane, ORF8), immune response (NSP1, NSP5, NSP15, NSP16, ORF6, ORF7a, ORF9b), replication (NSP3, NSP4, NSP7, NSP8, NSP9, NSP10, NSP12, NSP13, NSP14, Nucleoprotein), cellular degradation (NSP2, NSP6) and pathogenesis (ORF3a). The distribution of potential therapeutic indication of the drugs across the disease area for inhibiting the functions of 24 SARS-CoV2 protein was analysed for top 10 and bottom 10 drugs. It was observed that the top scored drugs for proteins involved in cell cycle showed therapeutic indication for infectious disease and neurology diseases whereas the least scored drugs showed therapeutic indications for oncology and also infectious disease. In case of immune response related proteins, the drugs among the top scored drugs had neurological therapeutic indication and drugs with least score had therapeutic indication for infectious diseases. In case of viral replication processes, the top scored drugs were related to oncology disease area and least scored drugs were related to infectious diseases. The cellular degradation category showed drugs with therapeutic indications for disease areas namely pain among the top, infectious disease among the bottom and for pathogenesis it was observed to be neurology and blood disorder among the top and bottom respectively.
Among the structural proteins, the envelope protein plays a vital role in the morphogenesis and assembly of the viral particles [54, 55]. The best molecules for this protein were obtained from different types of therapeutic indications namely liver disease, pain management, diabetes, and hypercortisolism whereas the least binding molecules are from bacterial infection, vitamin B12 deficiency, and immune suppressant agents. The function of the membrane protein is similar to envelope proteins and it is involved in the assembly and morphogenesis of the viral particles [56, 57]. The best active molecules for these targets are mainly from asthma, migraine, and inflammation therapeutic indications, and the least binding molecules are showed therapeutic indications for liver disease, anaemia, and melanoma. Spike protein is important in SARS-CoV2 infection and transmission of viral genetic material into the human [58, 59]. Anticancer, anti-inflammatory and antidiabetic molecules were identified as the best-screened molecules, the molecules that are used for bacterial infection, and immunosuppressants are identified as the least active molecules. The nucleoprotein involves in RNA transcription and viral replication [60, 61]. The antiviral and anticancer molecules were identified as the best active molecules and the anti-depressive and liver disease molecules were considered as the least active molecules. A total of 15 not structural proteins were taken for the study where NSP11 was not considered due to its smaller size and lack of binding cavity. The NSP1 is important for host cell modification [62, 63]. The best molecules are mainly from the drugs used for pain, cardiovascular disease, anticancer, and migraine. The drugs used for bacterial infection and vitamin B12 deficiency are identified as the least active molecules. NSP2 plays important role in viral infection [64, 65]. The virtual screening results revealed that the drug molecules for antibacterial, migraine and chronic hepatitis C are identified under the best active molecules and the least active molecules are mainly from the anaesthetic agent, liver disease, and kidney disease. NSP3 is important for viral replication [66, 67]. The molecules for anticancer, and migraines are among the best active molecules and mainly molecules for liver disease, urinary tract infection and melanoma have fallen in the least active molecules. NSP4 cleaves the replicase polyprotein at the C-terminus at 11 different sites [68, 69]. The radotinib (anticancer molecule) has been identified as the best active compound along with therapeutic indications for asthma, cardiovascular disease etc. The drugs used for hypertension, muscle dysfunction and cystic fibrosis have been identified as the least active molecules. NSP5 (3CLpro) recognizes substrates containing the core sequence [70, 71]. Drugs used for bacterial infection, hypertension, cancer is identified as the most active molecules. The drugs that are used for depression, fungal infection is identified as the least active molecules. NSP6 plays a vital role in autophagosome and membrane vesicle formation [72-74]. The best active molecules are mainly from cancer treatment, antibacterial, allergy and the least active molecules are from liver disease, hypertension and melanoma. NSP7, NSP8, and NSP9 proteins are majorly involved in viral infection [75-77]. The anticancer, anti-inflammatory and antiviral molecules are identified as the most active molecules and antibacterial drugs, active vitamin D are identified as the least active molecules. NSP10 is majorly involved in viral transcription [78, 79]. The drugs that are used for Parkinson’s disease, hypertension and central nervous system is identified as the most active molecules and drugs that are used for obesity, schizophrenia is screened as the least active molecule. NSP12 helps in viral RNA replication and transcription [80, 81]. Drugs are used for migraines, cancer, and anti-inflammation are identified as the most active molecules. The drugs that are involved in vitamin deficiency, immunosuppressants is identified as the least active molecules. NSP13 with zinc-binding domain in N-terminus is a multi-functional protein [82, 83]. Virtual screening analysis has shown that the anticancer molecules are the most active molecules and the antibacterial molecule was considered as the least active molecule. NSP14 is involved in the unwinding activity of RNA from 5' to 3' polarity [84, 85]. The anticancer molecules with drugs for migraine were identified as the best active molecules and the molecules used for vitamin B12 deficiency, bacterial infection was identified as the least active molecules. NSP15 protein is an endoribonuclease enzyme that cleaves the viral RNA and invades the host immune system [86, 87]. The anticancer, drugs for lung disease and pain-killers were identified as the best active molecules and the molecules that are used as antihypertensive, for cystic fibrosis, and immunosuppressant that are identified as active molecules. NSP16 protein actively participated in viral mRNAs cap methylation [88, 89]. The drugs used for anticancer, central nervous system and pneumonia were among the active molecules and the molecules which are involved in liver disease, antiseptic was considered as the least active molecules. From the accessory proteins selected, the ORF3a protein molecule is involved in controlling up-regulates expression of fibrinogen subunits FGA, FGB, and FGG [90, 91]. The anticancer and antibacterial drugs used for migraine are identified as the most active molecules whereas some molecules that are used for liver disease and ant depressive were identified as the least active molecules. The ORF6 is responsible for multiple viral activities [92, 93]. The drugs used for antibacterial, migraine, anticancer were identified as the best active molecules and the drug molecules that are used as antiseptic and aesthetic were identified as the least active molecules. The ORF7a protein involves in virus replication in cell culture [94, 95]. The most active compounds are pain relievers and anti-diabetic molecules whereas the least active molecules are the drugs for vitamin B12 deficiency. The ORF8 protein is responsible for host-virus interaction [96, 97]. The molecules with therapeutic indications for central nervous system, antiviral, anti-inflammation and anticancer were observed among the most active molecules and the least active molecules were those compounds used for treating cancer. Finally, the ORF9B protein inhibits the host's innate immune response [98, 99]. The most active compounds are majorly for migraine, antibacterial and anticancer and the least active molecules for liver disease and anti-depressive molecules. According to this study, the majority of the active compounds have anticancer, pain, migraine, and anti-inflammatory therapeutic properties, while the least active compounds have anti-depressive, vitamin deficiency molecules, and antiseptics therapeutic properties. This gives an insight into the group of drugs that will can have therapeutic indications towards SARS-CoV2 targets and can be repurposed for developing potential leads for the treatment of COVID 19. In addition, it also narrows downs the category of drugs which need not be considered for repurposing against SARS-CoV2. This indicates that drug repurposing approach can be an effective approach for targeting the multiple targets for SARS-CoV2.