Integrated computational tools for identification of CCR5 antagonists as potential HIV-1 entry inhibitors: homology modeling, virtual screening, molecular dynamics simulations and 3D QSAR analysis.
Using integrated in-silico computational techniques, including homology modeling, structure-based and pharmacophore-based virtual screening, molecular dynamic simulations, per-residue energy decomposition analysis and atom-based 3D-QSAR analysis, we proposed ten novel compounds as potential CCR5-dependent HIV-1 entry inhibitors. Via validated docking calculations, binding free energies revealed that novel leads demonstrated better binding affinities with CCR5 compared to maraviroc, an FDA-approved HIV-1 entry inhibitor and in clinical use. Per-residue interaction energy decomposition analysis on the averaged MD structure showed that hydrophobic active residues Trp86, Tyr89 and Tyr108 contributed the most to inhibitor binding. The validated 3D-QSAR model showed a high cross-validated rcv2 value of 0.84 using three principal components and non-cross-validated r2 value of 0.941. It was also revealed that almost all compounds in the test set and training set yielded a good predicted value. Information gained from this study could shed light on the activity of a new series of lead compounds as potential HIV entry inhibitors and serve as a powerful tool in the drug design and development machinery.
School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4001, South Africa.
Suri
S
Moonsamy
School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4001, South Africa.
Radha Charan
RC
Dash
School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4001, South Africa. soliman@ukzn.ac.za.
Mahmoud E S
ME
Soliman
D000595:Amino Acid Sequence; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes / Q000737:chemistry; D015195:Drug Design; D055808:Drug Discovery; D023581:HIV Fusion Inhibitors / Q000737:chemistry*; D015497:HIV-1 / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D057166:High-Throughput Screening Assays; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D000077592:Maraviroc; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D025341:Principal Component Analysis; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D019713:Receptors, CCR5 / Q000737:chemistry; D054852:Small Molecule Libraries / Q000737:chemistry*; D013816:Thermodynamics; D014230:Triazoles / Q000737:chemistry; D014584:User-Computer Interface; D053586:Virus Internalization / Q000187:drug effects
D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D023581:HIV Fusion Inhibitors; D019713:Receptors, CCR5; D054852:Small Molecule Libraries; D014230:Triazoles; D000077592:Maraviroc