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Molecular docking, QSAR and ADMET basedmining of natural compounds against primetargets of HIV

AIDS is one of the multifaceted diseases and this underlying complexity hampers its complete cure. The toxicity of existing drugs and the emergence of the multidrug-resistant virus make the treatment worse. The development of effective, safe, and low-cost anti-HIV drugs is among the top global priority. Exploration of natural resources may give a ray of hope to develop new anti-HIV leads. Among the various therapeutic targets for HIV treatment, reverse transcriptase, protease, integrase, GP120, and ribonuclease are the prime focus.


HIV structure with prime targets which are involved in its replication. 3D structure of selected targets with their PDB ID.


In the present study, they predicted potential plant-derived natural molecules for HIV treatment using a computational approach, i.e. molecular docking, quantitative structure-activity relationship (QSAR), and ADMET studies. Receptor-ligand binding studies were performed using three different software for precise prediction–Discovery studio 4.0, Schrödinger, and Molegrow virtual docker. Docking scores revealed that Mulberrosides, Anolignans, Curcumin, and Chebulic acid are promising candidates that bind with multi targets of HIV, while Neo-andrographolide, Nimbolide, and Punigluconin were target-specific candidates. Subsequently, QSAR was performed using biologically proved compounds which predicted the biological activity of compounds. They identified Anolignans, Curcumin, Mulberrosides, Chebulic acid, and Neo-andrographolide as potential natural molecules for HIV treatment from results of molecular docking and 3D-QSAR. In Silico ADMET studies showed drug-likeness of these lead molecules. Structure similarities of identified lead molecules were compared with identified marketed drugs by superimposing both the molecules. Using in silico studies, they have identified few best-fit molecules of natural origin against identified targets which may give new drugs to combat HIV infection after wet lab validation.


Overall work flow followed for the screening of the natural inhibitors against prime targets of HIV.

AIDS is a life-threatening disease caused by the human immunodeficiency Virus (HIV) (Genus: lentivirus; Subgroup: retrovirus). This disease is highly complex and includes multiple components. The complexity of the dis-ease lies in the growth and progression cycle of the virus as well as the involvement of a compromised immune system. The long latent phase of the virus, high mutational and replication rates which lead to drug resistance, and extensive genetic diversity caused difficulty in early detection of the disease as well as the complete eradication of infection. Multi-targeted comprehensive therapies are required to address these interactive factors. The current generation of anti-HIV drugs only suppressed viral replication. The inhibition is not permanent and only prolongs the life of AIDS patients (https://aidsinfo.nih.gov/news/79/fauci–aids-therapies-must-address-complexity-of-hiv-disease-process%0A%0A). On the other hand, the current synthetic inhibitors also cause several side effects. Phytochemicals offer a more reliable and safe alternative therapeutic approach for AIDS. Plant compounds possess the potential to modulate multiple targets synergistically and have polyvalent therapeutic properties. Plants are the repository and factory of such diverse bioactive compounds which can be developed as novel future drugs.


Top scoring five ligands which are common in all three softwares against key targets of HIV.

Various plant-derived compounds as Andrographolide, Glycyrrhizin, Curcumin,Chebulic acid, etc. have demonstrated antiviral properties and some of them are in the clinical trials. Extracts and compounds from Phyllanthus niruri, Calophyllum spp, Glycyrrhiza glabrate under trial for HIV. Mining of particular compound from a large pool of diverse bioactive molecules containing medicinal plants demands effort, time, and high expenses. The complexity of the process can be condensed by using computational approaches like molecular docking, quantitative structure-activity relation (QSAR) and pharmacophore, etc.



Top docked natural compounds with key targets of HIV. (a) molecular interaction between reverse transcriptase and anolignan b, (b) interaction between gp 120 and curcumin, (c) interaction between integrase and curcumin, (d) interaction between protease and mulberroside c, (e) interaction between ribonuclease and chebulic acid.


Molecular docking is used for screening of the potential molecules from a large data-set and further, QSAR modeling is essentially required to predict and classify their biological activities. Based on structural and physicochemical similarities, QSAR model predicts the biological activity. Validation of developed QSAR model is necessary to test the reliability and goodness of fit, which is performed by internal or external validation. Further, the robustness and reliability of the developed model can be defined by applicability domain analysis, which spots the outliers and strengthen the model. In the present study, they selected 22 phytomolecules as ligands against five key receptors of HIV. The receptor-ligand binding study was performed using three different software. Based on the docking study, the identified potent molecules were further subjected to 3D-QSAR and in silico ADMET studies. Selection and validation of the QSAR model were conducted by determining MAE values and the applicability domain approach.



Predicted and observed biological activity (pIC50) for training and test set molecules of QSAR study. (a) reverse transcriptase inhibitors (b) entry inhibitors (c) integrase inhibitors (d) protease inhibitors.


Finally, the potent molecules from ligand library which showed a high binding affinity towards at least one target and having compliance with validated QSAR and ADMET parameters distinctively identified, which would serve as essential candidates for anti-HIV drug discovery1.


  1. Vora, J. et al. (2019). Molecular docking, QSAR and ADMET based mining of natural compounds against prime targets of HIV. Journal of biomolecular structure and dynamics, 37 (1), s. 131–146. doi:10.1080/07391102.2017.1420489

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