Identification of Novel HIV 1- Protease Inhibitors: Application of Ligand and Structure Based Pharmacophore Mapping and Virtual Screening

Abstract

A combined ligand and structure-based drug design approach provides a synergistic advantage over either methods performed individually. Present work bestows a good assembly of ligand and structure-based pharmacophore generation concept. Ligand-oriented study was accomplished by employing the HypoGen module of Catalyst in which we have translated the experimental findings into 3-D pharmacophore models by identifying key features (four point pharmacophore) necessary for interaction of the inhibitors with the active site of HIV-1 protease enzyme using a training set of 33 compounds belonging to the cyclic cyanoguanidines and cyclic urea derivatives. The most predictive pharmacophore model (hypothesis 1), consisting of four features, namely, two hydrogen bond acceptors and two hydrophobic, showed a correlation (r) of 0.90 and a root mean square of 0.71 and cost difference of 56.59 bits between null cost and fixed cost. The model was validated using CatScramble technique, internal and external test set prediction. In the second phase of our study, a structure-based five feature pharmacophore hypothesis was generated which signifies the importance of hydrogen bond donor, hydrogen bond acceptors and hydrophobic interaction between the HIV-1 protease enzyme and its inhibitors. This work has taken a significant step towards the full integration of ligand and structure-based drug design methodologies as pharmacophoric features retrieved from structure-based strategy complemented the features from ligand-based study hence proving the accuracy of the developed models. The ligand-based pharmacophore model was used in virtual screening of Maybridge and NCI compound database resulting in the identification of four structurally diverse druggable compounds with nM activities.

Pharmacophore-driven identification of N-methyl-D-receptor antagonists as potent neuroprotective agents validated using in vivo studies

“…Though a thoroughly examined pharmacophore model contains vital chemical features accountable for biological activities of potential drugs, it can be used as an input for a database search. As mentioned before, the hypothesis with the considerable score was utilized as an input for obtaining effective molecules from the databases such as National Cancer Institute (NCI) and Maybridge [ 33 ]. The “best conformer generation method” was used for retrieving the conformers of every molecule with an energy threshold of 20 kcal/mol.…”

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“…Primary features, including A, D and H feature, were displayed in all the possible interactive points available at the binding site. Then, neighboring primary features within 2.00 Å were clustered to the same features, and multiple SBP models were generated by random combination of 4 to 8 pharmacological features from the clustering results 19 . Ev features were added based on residues in binding site.…”

Squaryl Molecular Metaphors – Application to Rational Drug Design and Imaging Agents

“…This class of inhibitors also contained the diol functionality as a transition state mimic to interact with the catalytic aspartates. Several inhibitors based on these concepts were developed and found to be potent against HIV proteases [220]. To date, these inhibitors have not yet been approved for HIV therapy.…”