Structure-based drug design of non-nucleoside inhibitors for wild-type and drug-resistant HIV reverse transcriptase

Chen, Mao; Sudbeck, Elise A.; Venkatachalam, T. K.; Uckun, Fatih M.

doi:10.1016/s0006-2952(00)00408-1

Cited by 68 publications

(64 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Several crystal structures of HIV-1 RT in the apo form [15] and in complex with different NNRTIs were published [16][17][18][19][20][21][22][23][24][25][26][27][28] and successful structure-based design studies leading to the development of active NNRTIs have been reported [29]. However, no crystal structure for the RT-pyridinone complex is available.…”

Section: Introductionmentioning

confidence: 99%

Quantitative Structure–activity Relationship Analysis of Pyridinone HIV-1 Reverse Transcriptase Inhibitors using the k Nearest Neighbor Method and QSAR-based Database Mining

Medina‐Franco

Gelbukh

Oloff

et al. 2005

J Comput Aided Mol Des

View full text Add to dashboard Cite

We have developed quantitative structure-activity relationship (QSAR) models for 44 non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) of the pyridinone derivative type. The k nearest neighbor (kNN) variable selection approach was used. This method utilizes multiple descriptors such as molecular connectivity indices, which are derived from two-dimensional molecular topology. The modeling process entailed extensive validation including the randomization of the target property (Y-randomization) test and the division of the dataset into multiple training and test sets to establish the external predictive power of the training set models. QSAR models with high internal and external accuracy were generated, with leave-one-out cross-validated R2 (q2) values ranging between 0.5 and 0.8 for the training sets and R2 values exceeding 0.6 for the test sets. The best models with the highest internal and external predictive power were used to search the National Cancer Institute database. Derivatives of the pyrazolo[3,4-d]pyrimidine and phenothiazine type were identified as promising novel NNRTIs leads. Several candidates were docked into the binding pocket of nevirapine with the AutoDock (version 3.0) software. Docking results suggested that these types of compounds could be binding in the NNRTI binding site in a similar mode to a known non-nucleoside inhibitor nevirapine.

show abstract

Section: Introductionmentioning

confidence: 99%

Quantitative Structure–activity Relationship Analysis of Pyridinone HIV-1 Reverse Transcriptase Inhibitors using the k Nearest Neighbor Method and QSAR-based Database Mining

Medina‐Franco

Gelbukh

Oloff

et al. 2005

J Comput Aided Mol Des

View full text Add to dashboard Cite

show abstract

“…However, the single K103N mutation can still confer crossresistance to most, if not all, of the members of this subclass (8). Thus, the continuous challenge posed by the emergence of HIV-1-resistant mutants highlights the need to develop third generation inhibitors with yet more favorable binding properties to the wild type and mutated enzymes (9).…”

mentioning

confidence: 99%

The Stereoselective Targeting of a Specific Enzyme-Substrate Complex Is the Molecular Mechanism for the Synergic Inhibition of HIV-1 Reverse Transcriptase by (R)-(−)-PPO464

Maga

Ramunno

Nacci

et al. 2001

Journal of Biological Chemistry

View full text Add to dashboard Cite

The human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase (RT) inhibitor pyrrolopyridooxazepinone (PPO) derivative, (؎)-PPO294, was shown to be active toward wild type and mutated HIV-1 RT and to act synergistically in combination with 3-azido-3-deoxythymidine (Campiani, G., Morelli, E., Fabbrini, M., Nacci, V., Greco, G., Novellino, E., Ramunno, A., Maga, G., Spadari, S., Caliendo, G., Bergamini, A., Faggioli, E., Uccella, I., Bolacchi, F., Marini, S., (1999) J. Med. Chem. 42, 4462-4470). The (؎)-PPO294 racemate was resolved into its pure enantiomers, and the absolute configuration was determined by x-ray analysis. The virus-encoded HIV-1 1 reverse transcriptase (RT) is essential for the viral replication cycle and therefore represents a logical target for antiviral chemotherapy (1, 2). Recently, a class of inhibitors targeted to the viral RT, the so-called NNRTIs, have gained a definitive place in the treatment of HIV-1 infections along with NRTIs and PIs (3). These compounds, despite their different chemical structures, are highly specific for HIV-1 RT and bind to the enzyme at the same allosteric site close to, but distinct from, the catalytic site, behaving as typically noncompetitive inhibitors with respect to the different substrates of the polymerization reaction. The NNRTIs nevirapine, delavirdine, and the most recently licensed, efavirenz (Fig. 1), are currently used in clinical practice. First generation NNRTIs, such as nevirapine, were identified by extensive random screening of different molecules. However, given their very similar mode of action and their unique binding site in the RT enzyme, the occurrence of just a few single amino acid substitutions in the RT gene can confer resistance to most of the first generation NNRTIs such as nevirapine (4). Accumulating knowledge about the resistance mutations selected by these compounds during chemotherapy as well as the resolution of crystallographic structures of different complexes of HIV-1 RT bound to NNRTIs (5, 6) allowed the rational design of second generation molecules, such as efavirenz, with improved potency against the wild type enzyme and several resistant forms (7). However, the single K103N mutation can still confer crossresistance to most, if not all, of the members of this subclass (8). Thus, the continuous challenge posed by the emergence of HIV-1-resistant mutants highlights the need to develop third generation inhibitors with yet more favorable binding properties to the wild type and mutated enzymes (9).Triple drug combinations have been shown to suppress plasma HIV-1 load for periods of time significantly longer than monotherapy or dual therapy, allowing CD4T cell increase, * This work was supported in part by ISS-Programma Nazionale di Ricerca sull' AIDS Contract 30C.70 (to S. S. and G. M.), 30C.34 (to F. B., S. P., and M. Z.), and 40C.65 (to V. N. and G. C.); by the Consiglio Nazionale delle Ricerche Target Project on Biotechnology (to S. S.); by Universita' di Siena Grant PARR 99 (to G. C.); and by contrac...

show abstract

“…Therefore, development of novel NNRTIs with enhanced therapeutic profile and different resistance mutation profiles is urgently required to successfully employ this class in combination therapy. Several crystal structures of HIV-1 RT in the apo form and in complex with different NNRTIs were published and successful structure based design studies leading to the development of active NNRTIs have been reported (Mao et al, 2000). Ongoing effort in this direction 'hypothetical 3D pharmacophore model' for NNRTIs was built using a combined ligand-and structure-based molecular modeling approach consisting of five features: three hydrophobic groups, one hydrogen bond acceptor, and one hydrogen bond donor (Barreca et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

QSAR modeling of the inhibition of reverse transcriptase enzyme with benzimidazolone analogs

Kumar¹,

Singh²,

Tiwari³

2010

Med Chem Res

View full text Add to dashboard Cite

The reverse transcriptase inhibitory activity of a set of 27 compounds of benzimidazolone analogs is predicted, applying the quantitative structure activity relationship (QSAR) theory. The physicochemical properties representing the 2D and 3D features of molecules were calculated from MOE 2008.10 software. For building the regression models three different variable selection approaches namely, enhanced replacement method (ERM), forward stepwise regression (FSWR), genetic function approximation (GFA) were used and compared to predict the inhibition activity. The ERM outperform at four variables against both FSWR and GFA as evidenced by statistical parameters (n = 21, r training 2 = 0.8864, Q 2 = 0.8243, r pred 2 = 0.6423, r m 2 = 0.5614). The derived QSAR models have shown that hydrophobicity and size of molecules holds promise for rationalizing the reverse transcriptase inhibitory activity of benzimidazolone analogs. The result of present study may help in designing analogs with better activity.

show abstract

Structure-based drug design of non-nucleoside inhibitors for wild-type and drug-resistant HIV reverse transcriptase

Cited by 68 publications

References 60 publications

Quantitative Structure–activity Relationship Analysis of Pyridinone HIV-1 Reverse Transcriptase Inhibitors using the k Nearest Neighbor Method and QSAR-based Database Mining

Quantitative Structure–activity Relationship Analysis of Pyridinone HIV-1 Reverse Transcriptase Inhibitors using the k Nearest Neighbor Method and QSAR-based Database Mining

The Stereoselective Targeting of a Specific Enzyme-Substrate Complex Is the Molecular Mechanism for the Synergic Inhibition of HIV-1 Reverse Transcriptase by (R)-(−)-PPO464

QSAR modeling of the inhibition of reverse transcriptase enzyme with benzimidazolone analogs

Contact Info

Product

Resources

About