ABSTRACT
In quite a few diseases, drug resistance due to target variability poses a serious problem in pharmacotherapy. This is certainly true for HIV, and hence, it is often unknown which drug is best to use or to develop against an individual HIV strain. In this work we applied 'proteochemometric' modeling of HIV Non-Nucleoside Reverse Transcriptase (NNRTI) inhibitors to support preclinical development by predicting compound performance on multiple mutants in the lead selection stage. Proteochemometric models are based on both small molecule and target properties and can thus capture multi-target activity relationships simultaneously, the targets in this case being a set of 14 HIV Reverse Transcriptase (RT) mutants. We validated our model by experimentally confirming model predictions for 317 untested compound-mutant pairs, with a prediction error comparable with assay variability (RMSE 0.62). Furthermore, dependent on the similarity of a new mutant to the training set, we could predict with high accuracy which compound will be most effective on a sequence with a previously unknown genotype. Hence, our models allow the evaluation of compound performance on untested sequences and the selection of the most promising leads for further preclinical research. The modeling concept is likely to be applicable also to other target families with genetic variability like other viruses or bacteria, or with similar orthologs like GPCRs.
Subject(s)
Drug Evaluation, Preclinical/methods , Models, Molecular , Proteomics/methods , Reverse Transcriptase Inhibitors/analysis , Reverse Transcriptase Inhibitors/chemistry , Amino Acid Sequence , Binding Sites , Databases as Topic , HIV Reverse Transcriptase/antagonists & inhibitors , HIV Reverse Transcriptase/chemistry , Humans , Ligands , Molecular Sequence Data , Mutation/genetics , Reproducibility of Results , Reverse Transcriptase Inhibitors/pharmacologyABSTRACT
TMC114, a potent novel HIV-1 protease inhibitor, remains active against a broad spectrum of mutant viruses. In order to bind to a variety of mutants, the compound needs to make strong, preferably backbone, interactions and have enough conformational flexibility to adapt to the changing geometry of the active site. The conformational analysis of TMC114 in the gas phase yielded 43 conformers in which five types of intramolecular H-bond interactions could be observed. All 43 conformers were subject to both rigid and flexible ligand docking in the wild-type and a triple mutant (L63P/V82T/I84V) of HIV-1 protease. The largest binding energy was calculated for the conformations that are close to the conformation observed in the X-ray complexes of TMC114 and HIV-1 protease.
Subject(s)
HIV Protease Inhibitors/chemistry , HIV Protease/metabolism , Sulfonamides/chemistry , Algorithms , Binding Sites , Computer Simulation , Crystallography, X-Ray , Darunavir , Gases/chemistry , HIV Protease Inhibitors/pharmacology , Hydrogen Bonding , Ligands , Models, Molecular , Molecular Conformation , Monte Carlo Method , Sulfonamides/pharmacology , Thermodynamics , Water/chemistryABSTRACT
Human immunodeficiency virus type 1 (HIV-1) protease has been continuously evolving and developing resistance to all of the protease inhibitors. This requires the development of new inhibitors that bind to the protease in a novel fashion. Most of the inhibitors that are on the market are peptidomimetics, where a conserved water molecule mediates hydrogen bonding interactions between the inhibitors and the flaps of the protease. Recently a new class of inhibitors, lysine sulfonamides, was developed to combat the resistant variants of HIV protease. Here we report the crystal structure of a lysine sulfonamide. This inhibitor binds to the active site of HIV-1 protease in a novel manner, displacing the conserved water and making extensive hydrogen bonds with every region of the active site.
Subject(s)
HIV Protease Inhibitors/chemistry , HIV Protease/chemistry , Sulfonamides/chemistry , Binding Sites , Crystallography, X-Ray , HIV Protease/metabolism , HIV Protease Inhibitors/metabolism , Models, Molecular , Protein Structure, Tertiary , Sulfonamides/metabolismABSTRACT
Novel diarylpyrimidines (DAPY), which represent next generation of non-nucleoside reverse transcriptase inhibitors (NNRTIs), were synthesized and their activities against human immunodeficiency virus type I (HIV-1) assessed. Modulations at positions 2 and 6 of the left phenyl ring generated interesting derivatives of TMC278 displaying high potency against wild-type and mutant viruses compared to nevirapine and efavirenz. The pharmacokinetic profile of the best newly synthesized DAPY was evaluated and compared with TMC278 now in phase II clinical trials.
Subject(s)
HIV-1/drug effects , Nitriles/chemical synthesis , Nitriles/pharmacology , Pyrimidines/chemistry , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacology , Animals , Chromatography, High Pressure Liquid , Dogs , Female , Magnetic Resonance Spectroscopy , Male , Mass Spectrometry , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Rats , Rats, Wistar , Rilpivirine , Spectrophotometry, UltravioletABSTRACT
On the basis of structural data gathered during our ongoing HIV-1 protease inhibitors program, from which our clinical candidate TMC114 9 was selected, we have discovered new series of fused heteroaromatic sulfonamides. The further extension into the P2' region was aimed at identifying new classes of compounds with an improved broad spectrum activity and acceptable pharmacokinetic properties. Several of these compounds display an exceptional broad spectrum activity against a panel of highly cross-resistant mutants. Certain members of these series exhibit favorable pharmacokinetic profiles in rat and dog. Crystal structures and molecular modeling were used to rationalize the broad spectrum profile resulting from the extension into the P2' pocket of the HIV-1 protease.
Subject(s)
Benzoxazoles/chemical synthesis , Drug Resistance, Multiple, Viral , HIV Protease Inhibitors/chemical synthesis , HIV-1/drug effects , Sulfonamides/chemical synthesis , Thiazoles/chemical synthesis , Animals , Benzoxazoles/chemistry , Benzoxazoles/pharmacology , Binding Sites , Calorimetry , Cell Line , Crystallography, X-Ray , Dogs , Drug Stability , HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/pharmacology , Humans , In Vitro Techniques , Microsomes, Liver/metabolism , Models, Molecular , Rats , Rats, Wistar , Sulfonamides/chemistry , Sulfonamides/pharmacology , Thermodynamics , Thiazoles/chemistry , Thiazoles/pharmacologyABSTRACT
The screening of known HIV-1 protease inhibitors against a panel of multi-drug-resistant viruses revealed the potent activity of TMC126 on drug-resistant mutants. In comparison to amprenavir, the improved affinity of TMC126 is largely the result of one extra hydrogen bond to the backbone of the protein in the P2 pocket. Modification of the substitution pattern on the phenylsulfonamide P2' substituent of TMC126 created an interesting SAR, with the close analogue TMC114 being found to have a similar antiviral activity against the mutant and the wild-type viruses. X-ray and thermodynamic studies on both wild-type and mutant enzymes showed an extremely high enthalpy driven affinity of TMC114 for HIV-1 protease. In vitro selection of mutants resistant to TMC114 starting from wild-type virus proved to be extremely difficult; this was not the case for other close analogues. Therefore, the extra H-bond to the backbone in the P2 pocket cannot be the only explanation for the interesting antiviral profile of TMC114. Absorption studies in animals indicated that TMC114 has pharmacokinetic properties comparable to currently approved HIV-1 protease inhibitors.
