STRUCTURE-BASED DESIGN OF NOVEL RILPIVIRINE ANALOGUES AS HIV-1 NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS THROUGH QSPR AND MOLECULAR DOCKING
Keywords:
NNRTIs, Rilpivirine analogues, HIV-1 RT, QSPR, Molecular dockingAbstract
Objectives: The aim of this research is to investigate the better biological activities from Rilpivirine analogues based on their Quantitative Structure-Property Relationship (QSPR) and pharmacophore study.
Methods: In this study, we had designed six Rilpivirine analogues. The complementary aided-computational drug design and molecular docking was employed to find the best lead candidate. The drug-likeness properties of Rilpivirine analogues were defined by following the Rule of Five.
Results: The drug-likeness properties of Rilpivirine derivatives (RVN 1-6) were defined by the Rule of Five (RO5), which RVN3 compound showed the best RO5 score among others. However, the log P value of RVN1 and RVN4 are lower than 5, while RVN2, RVN3, RVN5 and RVN6 have log P values greater than 5. Based on the solubility, RVN1 and RVN4 compounds are more soluble than other analogues including Rilpivirine prototype (RVN). The topological polar surface area (TPSA) score of RVN1 and RVN4 showed greater scores compared to others. On the other hand, the TPSA score of all Rilpivirine analogues are below 140 Ã…2. The absorption, distribution, metabolism, and excretion (ADME) properties of Rilpivirine analogues were determined, according to blood brain barrier penetration were found within the range of-1.2 to-2.2, which RVN4 showed the lowest value compared to others, while RVN showed the highest value. The percentage of human intestinal absorption was observed 100% to all compounds. The plasma protein binding percentages was obtained within the range 99.03-99.57%. Moreover, the hydrogen bond donor contribution of all compounds was in the range 2-4 bonds, while the acceptor hydrogen bond was found 6 bonds from all compounds. The mutagenicity properties showed all compounds could cause mutagenic effect in long-term administration. The carcinogenicity tests were done in mouse showed positive results to all compounds, while carcinogenicity test in rat showed negative results upon all compound, except RVN3 which gave positive result. From molecular docking result, RVN 1 and RVN 4 showed higher potential inhibition activities to Reverse Transcriptase Human Immunodeficiency Virus Type 1 (HIV-1 RT) compared other analogues.
Conclusion: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have a great potential inhibition against HIV-1 RT. From high throughput computational approach, we suggested that RVN 1 and RVN 4 are the potential drug candidates which have better activity among other Rilpivirine derivatives.
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