title: 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.
authors.affiliation: Department of Pharmacy, Banasthali University, Banasthali, Rajasthan, India.
authors.forename: Divya
authors.initials: D
authors.lastname: Yadav
authors.forename: Sarvesh
authors.initials: S
authors.lastname: Paliwal
authors.forename: Rakesh
authors.initials: R
authors.lastname: Yadav
authors.forename: Mahima
authors.initials: M
authors.lastname: Pal
authors.forename: Anubhuti
authors.initials: A
authors.lastname: Pandey
mesh_terms: D020134:Catalytic Domain; D016208:Databases, Factual; D015195:Drug Design; D006146:Guanidines / Q000737:chemistry; D015658:HIV Infections / Q000188:drug therapy; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology*; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D021281:Quantitative Structure-Activity Relationship; D014508:Urea / Q000737:chemistry
chemical_list: D006146:Guanidines; D017320:HIV Protease Inhibitors; D008024:Ligands; D014508:Urea; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; C004711:dicyandiamido