Computational Studies for Selected Medicinal Plants against Dolutegravir using Ligand Based Pharmacophore, Molecular Docking, ADMET Predictionsand Molecular Dynamics Simulation
Andrew Rabontsi Motsilanyane, Zimbili Mkhize, Sphelele Sosibo
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ABSTRACT
Human immunodeficiency virus type 1 (HIV-1) is
the causative agent for acquired immunodeficiency syndrome (AIDS). In 2020,
South Africa recorded an estimated 8,2 million people living with HIV. This
extensive figure is a red flag to the country, as it causes serious economic burden
to its health care system. In the quest for finding a suitable inhibitor for
HIV-1 protease, computer aided drug design (CADD) approachstands out to be one
of the leading fields of study in pursuit of a new drug for HIV. The Lipinski rule of
five was applied in screening the ninety-two plant extracts from Ocium santum, Carica papaya, Persea Americana,
Azadirachta indica and Spondias mombin medicinal plants, and forty-six of the
compounds complied with this rule. Afterwards, a ligand-based pharmacophore was
constructed based on the active properties of the three (3) best binding
compound obtained from the screened ZINC compounds (Zinc_001456687980,
Zinc_001445792073 and Zinc_001461099137). Then the compounds with less than 0.5
RMSD were picked out. The best 10 compounds were docked and compared with a
drug that is already in the market, dolutegravir. 3, 5-di-O-galloyl-4-
O-digalloylquinic acid 3,5,4,4-Tetragqa (-8.6), epicatechin (-8) and quercitrin
(-8) obtained the highest binding affinity.Even though Tetragqa had the highest
binding affinity, it failing the test because of its large molecular weight.
The safety evaluation and other chemical parameters that included the
lipophilicity, physicochemical other properties of these compounds was
performed through SwissADME/T web server. On the best top three binding
compounds, only epicatechin (-8) had promising features of a drug candidate.
However, the remaining compounds from the best 10 compounds were also analysed
using the SwissADME/T tools, whereby two of them (juglanin and catechin) satisfied the ADMET prediction analysis.
Catechin showed some promising features as well after it displayed good
druglike properties, suitable for a novel compound. Lastly, molecular dynamics
simulation was then performed on the three lead compounds namely; epicatechin,
juglanin andcatechin against dolutegravir. The ligand protein interaction
between catechin and the protein displayed minimal shift of the protein during
the simulation that was performed over 100ns, signifying a strong complex association.
ABSTRACT
Human immunodeficiency virus type 1 (HIV-1) is
the causative agent for acquired immunodeficiency syndrome (AIDS). In 2020,
South Africa recorded an estimated 8,2 million people living with HIV. This
extensive figure is a red flag to the country, as it causes serious economic burden
to its health care system. In the quest for finding a suitable inhibitor for
HIV-1 protease, computer aided drug design (CADD) approachstands out to be one
of the leading fields of study in pursuit of a new drug for HIV. The Lipinski rule of
five was applied in screening the ninety-two plant extracts from Ocium santum, Carica papaya, Persea Americana,
Azadirachta indica and Spondias mombin medicinal plants, and forty-six of the
compounds complied with this rule. Afterwards, a ligand-based pharmacophore was
constructed based on the active properties of the three (3) best binding
compound obtained from the screened ZINC compounds (Zinc_001456687980,
Zinc_001445792073 and Zinc_001461099137). Then the compounds with less than 0.5
RMSD were picked out. The best 10 compounds were docked and compared with a
drug that is already in the market, dolutegravir. 3, 5-di-O-galloyl-4-
O-digalloylquinic acid 3,5,4,4-Tetragqa (-8.6), epicatechin (-8) and quercitrin
(-8) obtained the highest binding affinity.Even though Tetragqa had the highest
binding affinity, it failing the test because of its large molecular weight.
The safety evaluation and other chemical parameters that included the
lipophilicity, physicochemical other properties of these compounds was
performed through SwissADME/T web server. On the best top three binding
compounds, only epicatechin (-8) had promising features of a drug candidate.
However, the remaining compounds from the best 10 compounds were also analysed
using the SwissADME/T tools, whereby two of them (juglanin and catechin) satisfied the ADMET prediction analysis.
Catechin showed some promising features as well after it displayed good
druglike properties, suitable for a novel compound. Lastly, molecular dynamics
simulation was then performed on the three lead compounds namely; epicatechin,
juglanin andcatechin against dolutegravir. The ligand protein interaction
between catechin and the protein displayed minimal shift of the protein during
the simulation that was performed over 100ns, signifying a strong complex association.