همایش ملی بیوانفورماتیک ایران

صفحه اصلی / 4th international edition and 13th Iranian Conference on Bioinformatics

Computational study on the inhibitory potential of fungal metabolites against HIV-1 RT

نویسندگان :

Zohreh Sahhaf Razavi¹ Ali Ramazani² Armin Zarei³

1- دانشگاه زنجان 2- دانشگاه زنجان 3- دانشگاه زنجان

کلمات کلیدی :

HIV-1 RT،fungal metabolites،Protein structure،Molecular dynamics

چکیده :

The main target in creating antiviral drugs is viral polymerase, which is the center of viral replication. Research and development strategies for new antiviral drugs due to the increasing cost of drug research and development, random screening strategies of traditional drugs, and blind optimization of lead compounds consume a lot of resources and time. In recent years, new research strategies have been developed, including the use of natural fungal compounds. (Tsai, Lee et al. 2006, Choi 2012, Peng, Wang et al. 2022) Fungi of the order Sordariales belong to the phylum Ascomycota and are well-known producers of diverse secondary metabolites with significant environmental and biomedical importance. Secondary metabolites from this group exhibit various biological activities, including antimicrobial, antiviral, anticancer, and enzyme inhibition properties. Also, taking advantage of the potential of fungal secondary metabolites, it was decided to evaluate the inhibitory potency of 174 secondary metabolites from species of the order Sordariales against aspartyl viral polymerases, including HIV-1 reverse transcriptase (RT).(Hu and Hughes 2012, Charria-Girón, Surup et al. 2022, Nzimande, Makhwitine et al. 2023, Zhao, Wang et al. 2023) According to two-step virtual screening, ten of the 56 ligands that bind to the active center of the polymerase under investigation with autodock vina had an energy of -7 kcal/mol or less. In the next step, which was performed using autodock 4.2.6, only three ligands, 1 to 3, had the highest binding energy compared to ribavirin (reference drug).(Tarasova, Poroikov et al. 2018) The most significant interaction between hydrogen bonds and basic catalytic motifs, mediated by hydrophobic contacts, has been specifically shown by ligand 3. This implies that inhibiting the action of this enzyme can prevent viral multiplication, highlighting the potential applications of our findings and paving the way for the creation of novel antiviral medications. Further assessment was done to analyze how these ligands affected such polymerases in structure and dynamics through a molecular dynamics simulation of 100 nanoseconds.(Lindahl, Hess et al. 2001, Schüttelkopf and Van Aalten 2004) HIV-1 RT polymerase underwent considerable structural alterations upon binding to ligands 1 and 3, severely limiting its flexibility and functioning. Overall, ligand 3 was more effective than ribavirin at inhibiting viral replication and had the greatest impact on the polymerase. In addition, ligand 3 showed a promising profile of ADME/T, further supporting the fact that this compound could be a promising candidate for anti-HIV-1 RT activity and recommending its further preclinical exploration. The promising profile of ligand 3 instills confidence in its potential for antiviral drug development.