Antiviral activities QSARs

Drug binding is enhanced by hydrophobicity in that portion of the drug that binds to the pocket toe. Quantitative structure-activity relationship (QSAR) analysis of these compounds have consistently shown that the most predictive parameter of antiviral activity is a measure of hydrophobicity, the octanol water partition coefficient (logP) [80,82,85]. These studies have also consistently shown that there is no apparent correlation between electrostatic potential or dipole moment and potency. 

The quantum-chemical descriptors have also shown their usefulness in the development of QSARs for antiviral activities. The antirhinoviral activity of 9-benzylpurines has been correlated with Huckel MO-generated electronic parameters and empirical substituent constants [99]. The respective QSAR equation included the LUMO energy and the total 7r-electron energy (EnT) of the compounds as quantum-chemical descriptors ... 

Several studies using molecular connectivity have been performed on antiviral data. Tamm et al. developed data for the antiviral activity of alkyl-substituted benzimidazoles against the Lee strain of the flu virus. Hall and Kier have analyzed that data using chi indexes.It is found that the activity depends heavily on arrangement of substituents but not on the atom count. This analysis is revealed in the following QSAR. 

Wilkerson et al. [76] also synthesized and evaluated a series of unsym-metrical benzamide derivatives (19). They reported several QSAR models. QSAR 10 and 11 represents their best models for enzyme inhibition and antiviral activity. 

A parabolic dependence on hydrophobicity and molecular weight was noticed for the enzyme inhibitory activity in QSAR 10. K[ values used for deriving QSAR 10 were measured by inhibiting recombinant single-chain dimeric HIV protease. The same authors reported another statistically better QSAR model based on ClogP and the CMR term, however, C log P and CMR were highly collinear (r = 0.70). QSAR 11 reported for antiviral activity has less predic-... 

Gayathri et al. [86] conducted QSAR studies on enzyme inhibitory and antiviral activity of P2/P2 tetrahydropyrimidinones (22) data reported by Delucca etal. [87]. 

This QSAR showed a parabolic dependence of antiviral activity on hydropho-bicity. The activity first increases with increasing hydrophobidty up to an optimum value (log Po = 6.345) and then decreases with finther increase. The presence of CMR in the QSAR shows the importance of size dependent polarizability of these molecules for achieving good antiviral activity. The authors also analyzed individual datasets to study the effect of hydrophobidty of the molecules and reported three other QSAR [127]. It is of interest to note that out of the three QSAR, the first and third have a positive and negative C log P... 

QSAR 45-47 were developed [14] for the biological activities of a series of 2-aminobenzylstatin as a novel scissile bond replacement (39) reported by Bilhch et al. [159]. Several structural modifications including the introduction of a benzimidazole heterocycle into the inhibitor were studied. QSAR 45 was derived for enzyme inhibitory data. Antiviral activity measured as the concentration required to reduce the P24 antigen level in the supernatant of infected cell cultures by 50% HIV was modeled as QSAR 46. The antiviral activity measured as the concentration required to reduce the virus-induced cytopathic effect by 50% in MT-4 cells was modeled in QSAR 47. 

In another study Takashiro et al. [179] further studied the antiviral activity of AHPBA inhibitors (53). To reduce the peptide-like characteristics of the inhibitors, AHPBA and proline components were connected without using peptide bonds. QSAR 63 developed for the data indicated that electronreleasing Z-groups would enhance the activity [ 15]. A strong correlation with was observed even though it was a very small dataset. 

Kuz min VE, Artemenko AG, Polischuk PG et al (2005) Hierarchic system of QSAR models (ID D) on the base of simplex representation of molecular structure. JMol Model 11 457-467 Kuz min VE, Artemenko AG, Lozitsky VP et al (2002) The analysis of structure-anticancer and antiviral activity relationships for macrocyclic pyridinophanes and their analogues on the basis of 4D QSAR models (simplex representation of molecular structure). Acta Biochim Pol 49 157-168... 

Mendiratta, S. and Madan, A.K. (1994). Structure-Activity Study on Antiviral 5-Vinylpyrimidine Nucleoside Analogs Using Wiener s Topological Index. J.Chem.Inf.Comput.ScL, 34,867-871. Menziani, M.C. and De Benedetti, P.G. (1992). Molecular Mechanics and Quantum Chemical QSAR Analysis in Carbonic Anhydrase Heterocyclic Sulfonamide Interactions. Struct. CherrL,... 

Isatin (lH-indole-2,3-dione) is an endogenous compoimd identified in humans. This class of compoimds possesses a wide range of biological activities [35] that include antiallergic, anticancer, anticonvulsant, antidiuretic, antithrombotic, antitubercular, antiviral, anxiogenic, immunosuppressant, muscle relaxant, and sedative activities. Vine et aL [36] synthesized a variety of isatin derivatives (XII) and evaluated their cytotoxic activities against the human monocyte-Uke histiocytic lymphoma (U937) ceU line in vitro. We used these cytotoxic data to develop QSAR Eq. 11 (Table 5) ... 

QSAR 48 was derived [ 14] for the antiviral data of hydroxyethylene isostere derivatives (40) for inhibition of HIV protease in H9 human T-lymphocytes cells, reported by De Solms et al. [160]. One of the prototype pentapeptides (L-682,679) was modified at the carboxy terminus and mostly variations of the P2 amino acid and the elimination/replacement of the P3 amino acid were studied [160]. This model showed that overall bulky molecules would favor the activity. However, the X-substituents would have a negative steric effect. 

C2 symmetric amino diols and their tyrosine-derived analogs were some of the early leads on diol derivatives. Chen et al. [ 192] reported a detailed SAR study on Pi/Pj-substituted aminodiols (60). A high degree of correlation was observed between lipophilicity, measured by reverse-phase HPLC constant k and the cytotoxicity (CC50) of the compoimds (QSAR 68) [192]. It was also found that appropriate substitution at the para position of the P T phenyl group of 60 resulted in the identification of compounds that possess good antiviral and enzyme inhibitory activity and significantly decreased cytotoxicity [192]. 

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