Novel theoretically designed HIV-1 non-nucleoside reverse transcriptase inhibitors derived from nevirapine. 2014

Jinfeng Liu, and Xiao He, and John Z H Zhang
State Key Laboratory of Precision Spectroscopy and Department of Physics, Institute of Theoretical and Computational Science, East China Normal University, Shanghai, 200062, China.

A common problem with non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV-1 is the emergence of mutations in the HIV-1 RT, in particular Lys103 → Asn (K103N) and Tyr181 → Cys (Y181C), which lead to resistance to this entire class of inhibitors. In this study, we theoretically designed two new non-nucleoside HIV-1 RT inhibitors, Mnev-1 and Mnev-2, derived from nevirapine, in order to reduce the resistance caused by those HIV-1 RT mutations. The binding modes of Mnev-1 and Mnev-2 with the wild-type HIV-1 RT and its mutants (K103N and Y181C) were suggested by molecular docking followed by 20-ns molecular dynamics (MD) simulations in explicit water of those binding complexes (HIV-1 RTs with the new inhibitors). A molecular mechanics/generalized Born surface area (MM/GBSA) calculation was carried out for multiple snapshots extracted from the MD trajectory to estimate the binding free energy. The results of the calculations show that each of the new inhibitors forms a stable hydrogen bond with His235 during the MD simulations, leading to tighter binding of the new inhibitors with their targets. In addition, the repulsive interaction with Cys181 in the Y181C-nevirapine complex is not present in the novel inhibitors. The binding affinities predicted using the MM/GBSA calculations indicate that the new inhibitors could be effective at bypassing the drug resistance of these HIV-1 RT mutants.

UI MeSH Term Description Entries
D008024 Ligands A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed) Ligand
D009154 Mutation Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations. Mutations
D011487 Protein Conformation The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. PROTEIN STRUCTURE, QUATERNARY describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). Conformation, Protein,Conformations, Protein,Protein Conformations
D004735 Energy Transfer The transfer of energy of a given form among different scales of motion. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 6th ed). It includes the transfer of kinetic energy and the transfer of chemical energy. The transfer of chemical energy from one molecule to another depends on proximity of molecules so it is often used as in techniques to measure distance such as the use of FORSTER RESONANCE ENERGY TRANSFER. Transfer, Energy
D006860 Hydrogen Bonding A low-energy attractive force between hydrogen and another element. It plays a major role in determining the properties of water, proteins, and other compounds. Hydrogen Bonds,Bond, Hydrogen,Hydrogen Bond
D001665 Binding Sites The parts of a macromolecule that directly participate in its specific combination with another molecule. Combining Site,Binding Site,Combining Sites,Site, Binding,Site, Combining,Sites, Binding,Sites, Combining
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D013499 Surface Properties Characteristics or attributes of the outer boundaries of objects, including molecules. Properties, Surface,Property, Surface,Surface Property
D015195 Drug Design The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis. Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs
D015394 Molecular Structure The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. Structure, Molecular,Molecular Structures,Structures, Molecular

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