Hydroxyalkynyl uracil derivatives as NNRTIs against HIV-1: in silico predictions, synthesis, docking and molecular dynamics simulation studies

Abstract

To improve rationally the efficacy of the non-nucleoside human immunodeficiency virus (HIV-1) inhibitors, it is important to have a precise and detailed understanding of the HIV-1 reverse transcriptase (RT) and inhibitor interactions. For the 1-[(2-hydroxyethoxy) methyl]-6-(phenylthio) thymine (HEPT) type of nucleoside reverse transcriptase inhibitors (NNRTIs), the H-bond between the N-3H of the inhibitor and the backbone carbonyl group of K101 represents the major hydrophilic interaction. This H-bond contributes to the NNRTI binding affinity. The descriptor analyses of different uracil derivatives proved their good cell internalization. The bioactivity score reflected higher drug likeness score and the ligands showed interesting docking results. All molecules were deeply buried and stabilized into the allosteric site of HIV-1 RT. For majority of molecules, residues Lys101, Lys103, Tyr181 and Tyr188 were identified as key protein residues responsible for generation of H-bond and major interactions were similar to all known NNRTIs while very few molecules interacted with residues Phe227 and Tyr318. The TOPKAT protocol available in Discovery Studio 3.0 was used to predict the pharmacokinetics of the designed uracil derivatives in the human body. The molecular dynamics (MD) and post-MD analyses results reflected that the complex HIVRT:5 appeared to be more stable than the complex HIVRT:HEPT, where HEPT was used as reference. Different uracil derivatives have been synthesized by using uracil as starting material and commercially available propargyl bromide. The N-1 derivative of uracil was further reacted with sodamide and different aldehydes/ketones bearing alkyl and phenyl ring to obtain hydroxyalkynyl uracil derivatives as NNRTIs.

Communicated by Ramaswamy H. Sarma

Keywords:

• Anti HIV
• drug target
• drug design
• in silico studies
• HIV

Disclosure statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Author contributions

Madhu Yadav designed, synthesized and purified all the compounds along with drafted the manuscript. Ritika Srivastava and Farha Naaz did computational study (Docking and ADMET analysis) of the compounds and edited the manuscript. Parth Sarthi Sen Gupta, Saroj Kumar Panda and Malay Kumar Rana performed MD simulations and analyzed the results. Ramendra K. Singh supervised this work.

Additional information

Funding

The author Madhu Yadav acknowledges financial support in the form of a Research Fellowship from the UGC grant, University of Allahabad, Allahabad, India.