IU Chemical Informatics Journal Club

Authors: Sergio R. Ribone, Mario A. Quevedo, Marcela Madrid, and Margarita C. Brin˜o´n

Journal: J. Chem. Inf. Model., Article ASAP

DOI: 10.1021/ci1001636

Publication Date (Web): December 6, 2010

Mutation in viral strains is becoming a major global health problem. A fast mutation in viruses makes it difficult to find the correct drugs for the new structure. It is vital to know what kinds of interactions are important in the complex of target-protein and drug-inhibitor compound. This understanding may help finding better drug candidates, or in case the target protein mutates knowing what physico-chemical properties to be sought for a new drug.

human immunodeficiency virus type 1 (HIV-1) is one of the widely studied virus. HIV-1 reverse transcriptases are the enzymes responsible for the replication of the virus and hence have been considered one of the main therapeutic targets for anti-HIV drugs used in the treatment of AIDS. Varieties of inhibitors are known to-date that bind to these enzymes. In the present paper authors S Ribone et al study the binding of several classes of nonnucleoside reverse transcriptase inhibitors (NNRTIs) to two types of HIV-1RTases: wild-type (wtRT) and a certain (K103N) mutant (mRT). For this exhaustive study, they use methods of molecular dynamics and energy decomposition. Then through a careful comparison between properties of these NNRTIs such as: hydrogen bonding, quantitative free energy analyses, molecular interactions in the binding pockets they studied each drug’s potency. The molecular basis of the interaction between NNRTIs and RT presented here provides a novel quantitative approach for the design of novel effective anti-HIV drugs and may be used as a general approach for other drug-discoveries.

The authors also mention that one of the mRT-compund complexes they studied was in fact later crystallographically resolved and deposited in the RCSB protein data bank (PDB). This leads to a situation where computational studies help finding new drug. Authors study the nonnucleoside reverse transcriptase inhibitors (NNRTIs) that elicit RT inhibition by binding to a pocket identified as the nonnucleoside inhibitors binding pocket (NNIBP). The NNRTIs studied here range from the first-generation inhibitors that are voluminous and rigid structures (e.g. nevirapine) to the imidoylthiourea (ITU) and subsequently to the more potent diaryltriazine (DATA) and diarylpyrimidine (DAPY) analogues. DATA and DAPY inhibitors are similar in volume but possess a central ring joining two flexible lateral rings. Crystallographic studies show that nevirapine binds in a butterfly-like conformation while ITU, most DATA, and DAPY inhibitors bind in a horseshoe conformation. The DAPYs have increased flexibility inside the binding site and are very potent inhibitors against both wild-type and mutated RT. The internal surface of NNIBP is predominantly hydrophobic. NNRTIs are known to establish extensive hydrophobic interactions with NNIBP residues, including van der Waals and π-π stacking interactions with aromatic amino acid side chains, and form hydrogen bonds with the backbones of hydrophilic residues.

The available experimental data before this paper suggested that mutations cause drug resistance by different mechanisms, among them impairment of inhibitor accessibility to the NNIBP, modification of critical intermolecular interactions, or introduction of steric hindrance. In the present work, authors present a detailed analysis of the structure, molecular interactions in the binding pocket, energetics, and dynamics of drugs ranging from first- to third-generation compounds, bound to wtRT and K103N mutated RT (mRT). The molecular dynamics simulations were followed by free energy decomposition analyses, targeting towards a quantitative structure-activity model correlating the binding energetics to the reported anti-HIV activities (EC50).

During the 3 ns molecular dynamics (MD) simulation, authors studied the hydrogen bonding either direct or solvent-water mediated between the compound and the residues of the binding pocket. They also studied the energy decomposition during the MD trajectories and found that the antiviral potencies of compounds against the enzymes were closely related to their van der Waals energetic components. The decrease in the potency/activity correlates with the increase in the van der Waals energy which is also in agreement in the experimental findings. The authors also found that the K103N mutation in the binding pocket results in an increase in the electrostatic and van der Waals energies, in agreement with the marked loss in inhibitory activity against the mutated RT strain. They establish a strong correlation between the van der Waals energetic component and the reported antiviral activity against wtR. The correlation suggests that higher potencies are expected for those compounds that establish hydrophobic contacts with the residues in the binding pocket and is in agreement with the high hydrophobicity of the NNIBP of wtRT. Finally, the authors studied in detail the torsion angle distributions and showed to enhance antiviral activity torsions at the central ring of the compounds have to maximize the π-π stacking interactions with the residues in the binding pocket.

In conclusion, the authors have studied in large details, the molecular interactions and the origins of the potency of the anti-HIV drugs. They have applied molecular docking and molecular dynamics techniques to study the binding interactions, flexibility, and free energies of binding of several NNRTIs complexed to wtRT and K103N mRT, and correlate these properties to their reported biological activities. Authors found that all ITU, DATA, and DAPY compounds studied show sustained hydrogen bonds with Lys101 residue in the binding pocket and in some cases also with Glu138 residues (However, the existence of this additional hydrogen bond does not correlate with a higher biological activity against wtRT). These two residues can therefore be regarded as important for the future drug-compound discoveries. They establish a linear relationship between the biological activity of all complexes and the van der Waals energetic component when bound to wtRT. This in their view can be regarded as a predictive tool for the design of effective inhibitors against wtRT. The K103N mutation modifies the electrostatic properties of the binding pocket. The authors show that RT inhibitors with activity against both wild-type and K103N mutated HIV strains show (a) hydrophobic interactions with the NNIBP, and (b) specific intermolecular interactions with a hydrophilic region in the lower part of the binding pocket. According to the correlation observed in this work, a potent inhibitor of wtRT must maximize its van der Waals interactions in the binding pocket.

The study presented here provides a valuable methodology for the rational design of effective inhibitors with better therapeutic profiles for the treatment of AIDS and in general for other pandemic diseases.

# posted by Harshad.Joshi : 8:59 PM