title: An in silico approach for identification of novel inhibitors as a potential therapeutics targeting HIV-1 viral infectivity factor.
abstract: Currently available antiviral drugs target the pol-encoded retroviral enzymes or integrases, in addition, inhibitors that target HIV-1 envelope-receptor interactions have also been recently approved. Recent understanding of the interactions between HIV-1 and host restriction factors has provided fresh avenues for development of novel antiviral drugs. For example, viral infectivity factor (Vif) now surfaced as an important therapeutic target in treatment of HIV infection. Vif suppresses A3G antiviral activity by targeting these proteins for polyubiquitination and proteasomal degradation. In the present study we analyzed the inhibitory potential of VEC5 and RN18 to inhibit the Vif-A3G interaction through protein- protein docking studies. Perusal of the study showed that, VEC5 and RN18 though inhibits the interaction however showed sub optimal potential. To overcome this set back, we identified 35 structural analogues of VEC5 and 18 analogues of RN18 through virtual screening approach. Analogue with PubCID 71624757 and 55358204 (AKOS006479723) -structurally akin to VEC5 and RN18 respectively showed much appreciable interaction than their respective parent compound. Evident from Vif-A3G; protein - protein docking studies, analogue PubCID 71624757 demonstrated 1.08 folds better inhibitory potential than its parent compound VEC5 while analogue PubCID 55358204 was 1.15 folds better than RN18. Further these analogues passed drug likeness filters and predicted to be non- toxic. We expect these analogues can be put to pharmacodynamic studies that can pave way the breakthrough in HIV therapeutics.
authors.forename: Chanda
authors.initials: C
authors.lastname: Sinha
authors.forename: Anuradha
authors.initials: A
authors.lastname: Nischal
authors.forename: Srinivas
authors.initials: S
authors.lastname: Bandaru
authors.forename: Priyadarshani
authors.initials: P
authors.lastname: Kasera
authors.forename: Ashish
authors.initials: A
authors.lastname: Rajput
authors.forename: Anuraj
authors.initials: A
authors.lastname: Nayarisseri
authors.affiliation: Department of Pharmacology and Therapeutics, King George's Medical University, (Erstwhile C.S.M. Medical University), Lucknow-226 003, India. sinha.chanda17@gmail.com.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Khattri
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000737:chemistry*; D001665:Binding Sites; D055808:Drug Discovery; D015497:HIV-1 / Q000737:chemistry*; D057166:High-Throughput Screening Assays; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D016415:Sequence Alignment; D055672:Static Electricity; D013329:Structure-Activity Relationship; D014584:User-Computer Interface; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D019380:Anti-HIV Agents; D054320:vif Gene Products, Human Immunodeficiency Virus; C514847:vif protein, Human immunodeficiency virus 1