Targeting ADA and HIV-1 Nef Protein with Protease Inhibitors: a Repurposing Strategy through Molecular Networking and an in silico Approach for Integrated Management of HIV Co-infected with Abdominal Tuberculosis

Background: The co-infection of HIV and abdominal TB poses a worldwide danger to humanity. This is because there are more strains of bacteria that are resistant to many classes of currently available medications. According to current findings, repurposing existing available medications will result in more effective functioning than using newly designed medications. Based on this fact, we hypothesised that the PI could be repurposed; we used Food and Drug Administration (FDA)-approved PI drugs to treat HIV co-infected patients with abdominal TB, and a computational study has been conducted. This comprises network analysis models to find their protein drug interaction (PDI) through a search tool for interacting chemicals (STICH) module of Cytoscape network analysis model followed by the screening of these drugs for their ADMET prediction and binding affinity with adenosine deaminase (ADA), a protein responsible for abdominal TB, and the HIV-1 Nef protein, responsible for the regulation of immune function (CD4+). The network analysis showed 13 nearest binding drugs of these proteins of interest. The ADMET study result showed the pharmacologically relevant parameters that have a significant effect on the binding affinity, bioavailability, and toxicity of PI. The top three scores achieved by PI against adenosine deaminase enzyme activity (PDB ID: 1A4M) are viz., -23.7919, -23.3529, and -22.6773 for Ritonavir, Tipranavir, and Atazanavir, respectively. The top three scores achieved by PI against HIV-1 Nef protein activity (PDB ID: 6URI) are viz., -28.7321, -28.4987, and -28.3155 for Atazanavir, Tipranavir, and Simeprevir, respectively. The active site of ADA and HIV-1 Nef proteins comprises amino acid residues such as for Tipranavir: Arene-Cation interaction (Phenyl and Pyridine)- Arg B1081, and Lys B1033 (1A4M) and Arene-Cation interaction (Pyridine and Phenyl)- Lys D11 and Arg D33; Sidechain acceptor Thr B40; Sidechain donor- Asp D30; Backbone donor- Ala B37 (6URI). Atazanavir: Arene-Cation interaction (Phenyl)- Lys A254 and Lys B1033; Sidechain acceptor - Arg A251 (1A4M). Thus, from the computational studies carried out, we could obtain hints for optimising the molecular selectivity of the PI to provide help in the design of new compounds via the repurposing strategy of the FDA-approved PI for effective treatment of co-morbidity with HIV and abdominal TB. However, further pharmacokinetics, pharmacodynamics, preclinical, and clinical studies permit the design of the new agents without undesirable interactions.