Series Of HIV-1 Protease Inhibitors Research Articles

Design, synthesis, and biological evaluation of novel HIV-1 protease inhibitors containing pyrrolidine-derived P2 ligands to combat drug-resistant variant

The design, synthesis, and biological evaluation of a novel series of HIV-1 protease inhibitors containing pyrrolidines with diverse linkers as the P2 ligands and various aromatic derivatives as the P2’ ligands were described. A number of inhibitors demonstrated potent efficacy in both enzyme and cellular assays, as well as relatively low cytotoxicity. In particular, inhibitor 34b with a (R)-pyrrolidine-3-carboxamide P2 ligand and a 4-hydroxyphenyl P2’ ligand displayed exceptional enzyme inhibitory activity with an IC50 value of 0.32 nM. Furthermore, 34b also exhibited robust antiviral activity against both wild-type HIV-1 and drug-resistant variant with low micromolar EC50 values. In addition, the molecular modelling studies revealed the extensive interactions between inhibitor 34b and the backbone residues of both wild-type and drug-resistant HIV-1 protease. These results suggested the feasibility of utilizing pyrrolidine derivatives as the P2 ligands and provided valuable information for further design and optimization of highly potent HIV-1 protease inhibitors.

Design and Evaluation of Novel HIV-1 Protease Inhibitors Containing Phenols or Polyphenols as P2 Ligands with High Activity against DRV-Resistant HIV-1 Variants.

With the increasing prevalence of drug-resistant variants, novel potent HIV-1 protease inhibitors with broad-spectrum antiviral activity against multidrug-resistant causative viruses are urgently needed. Herein, we designed and synthesized a new series of HIV-1 protease inhibitors with phenols or polyphenols as the P2 ligands and a variety of sulfonamide analogs as the P2' ligands. A number of these new inhibitors showed superb enzymatic inhibitory activity and antiviral activity. In particular, inhibitors 15d and 15f exhibited potent enzymatic inhibitory activity in the low picomolar range, and the latter showed excellent activity against the Darunavir-resistant HIV-1 variant. Furthermore, the molecular modeling studies provided insight into the ligand-binding site interactions between inhibitors and the enzyme cavity, and they sparked inspiration for the further optimization of potent inhibitors.

Synthesis and evaluation of potent human immunodeficiency virus 1 protease inhibitors with epimeric isopropanol as novel P1' ligands.

Aim: HIV-1 protease inhibitors regimens suffered from a number of drawbacks, among which, the most egregious issue was the growing emergence of drug-resistant strains. Materials & methods: The design strategy of maximizing the protease active site interactions with the inhibitor, especially promoting extensive hydrogen bonding with the protein backbone atoms, might be in favor of combating drug resistance. A series of HIV-1 protease inhibitors that incorporated enantiomeric isopropanols as the P1' ligands in combination with phenols as the P2 ligands were reported herein. Results: A number of inhibitors displayed potent protease enzyme inhibition activity. In particular, inhibitor 14c showed comparable potency as darunavir with IC50 value of 1.91nM and activity against darunavir-resistant HIV-1 variants. Conclusion: The new kind of HIV-1 protease inhibitors deserves further study.

Design, synthesis and biological evaluation of novel HIV-1 protease inhibitors with pentacyclic triterpenoids as P2-ligands

The design, synthesis and SAR study of a new series of HIV-1 protease inhibitors with pentacyclic triterpenoids as P2 ligands and phenylsulfonamide as P2′ ligands were discussed. These compounds exhibited micromolar inhibitory potency, among which compound T1c displayed HIV-1 protease inhibition with IC50 values of 0.12 μM, which was 67 times the inhibitory activity of its raw material Ursolic acid (8.0 μM).

Design and synthesis of potent HIV-1 protease inhibitors with (S)-tetrahydrofuran-tertiary amine-acetamide as P2−ligand: Structure−activity studies and biological evaluation

The design, synthesis, and SAR study of a new series of HIV-1 protease inhibitors incorporating stereochemically defined tetrahydrofuran-tertiary amine-acetamide P2-ligand are described. Various substituent effects on the tertiary amine P2-ligand and phenylsulfonamide P2′-ligand were investigated to maximize the ligand-binding site interactions in the protease active site. Most of inhibitors displayed low nanomolar to subnanomolar inhibitory potency. Inhibitor 20e containing N-(S-tetrahydrofuran)-N-(2-methoxyethyl)acetamide as P2-ligand along with 4-methoxylphenylsulfonamide as P2′-ligand displayed the most potent enzyme inhibitory activity (IC50 = 0.35 nM) and remarkably low cytotoxicity (CC50 = 305 μM).

Constructing Interconsistent, Reasonable, and Predictive Models for Both the Kinetic and Thermodynamic Properties of HIV-1 Protease Inhibitors.

Accumulated evidence suggests that the in vivo biological potency of a ligand is more strongly correlated with the binding/unbinding kinetics than the equilibrium thermodynamics of the protein-ligand interaction (PLI). However, the existing experimental and computational techniques are largely insufficient and limited in large-scale measurements or accurate predictions of the kinetic properties of PLI. In this work, elaborate efforts have been made to develop interconsistent, reasonable, and predictive models of the association rate constant (kon), dissociation rate constant (koff), and equilibrium dissociation constant (KD) of a series of HIV protease inhibitors with different structural skeletons. The results showed that nine Volsurf descriptors derived from water (OH2) and hydrophobic (DRY) probes are key molecular determinants for the kinetic and thermodynamic properties of HIV-1 protease inhibitors. To the best of our knowledge, this is the first time that interconsistent and reasonable models with strong prediction power have been established for both the kinetic and thermodynamic properties of HIV protease inhibitors.

Structure-based design of potent HIV-1 protease inhibitors with modified P1-biphenyl ligands: synthesis, biological evaluation, and enzyme-inhibitor X-ray structural studies.

We report the design, synthesis, X-ray structural studies, and biological evaluation of a novel series of HIV-1 protease inhibitors. We designed a variety of functionalized biphenyl derivatives to make enhanced van der Waals interactions in the S1 subsite of HIV-1 protease. These biphenyl derivatives were conveniently synthesized using a Suzuki-Miyaura cross-coupling reaction as the key step. We examined the potential of these functionalized biphenyl-derived P1 ligands in combination with 3-(S)-tetrahydrofuranyl urethane and bis-tetrahydrofuranyl urethane as the P2 ligands. Inhibitor 21e, with a 2-methoxy-1,1'-biphenyl derivative as P1 ligand and bis-THF as the P2 ligand, displayed the most potent enzyme inhibitory and antiviral activity. This inhibitor also exhibited potent activity against a panel of multidrug-resistant HIV-1 variants. A high resolution X-ray crystal structure of related Boc-derivative 17a-bound HIV-1 protease provided important molecular insight into the ligand-binding site interactions of the biphenyl core in the S1 subsite of HIV-1 protease.

Highly potent HIV-1 protease inhibitors with novel tricyclic P2 ligands: design, synthesis, and protein-ligand X-ray studies.

The design, synthesis, and biological evaluation of a series of HIV-1 protease inhibitors incorporating stereochemically defined fused tricyclic P2 ligands are described. Various substituent effects were investigated to maximize the ligand-binding site interactions in the protease active site. Inhibitors 16a and 16f showed excellent enzyme inhibitory and antiviral activity, although the incorporation of sulfone functionality resulted in a decrease in potency. Both inhibitors 16a and 16f maintained activity against a panel of multidrug resistant HIV-1 variants. A high-resolution X-ray crystal structure of 16a-bound HIV-1 protease revealed important molecular insights into the ligand-binding site interactions, which may account for the inhibitor's potent antiviral activity and excellent resistance profiles.

Molecular Dynamics Investigation on a Series of HIV Protease Inhibitors: Assessing the Performance of MM-PBSA and MM-GBSA Approaches

The binding free energies (ΔG(Bind)) obtained from molecular mechanics with Poisson-Boltzmann surface area (MM-PBSA) or molecular mechanics with Generalized Born surface area (MM-GBSA) calculations using molecular dynamics (MD) trajectories are the most popular procedures to measure the strength of interactions between a ligand and its receptor. Several attempts have been made to correlate the ΔG(Bind) and experimental IC(50) values in order to observe the relationship between binding strength of a ligand (with its receptor) and its inhibitory activity. The duration of MD simulations seems very important for getting acceptable correlation. Here, we are presenting a systematic study to estimate the reasonable MD simulation time for acceptable correlation between ΔG(Bind) and experimental IC(50) values. A comparison between MM-PBSA and MM-GBSA approaches is also presented at various time scales. MD simulations (10 ns) for 14 HIV protease inhibitors have been carried out by using the Amber program. MM-PBSA/GBSA based ΔG(Bind) have been calculated and correlated with experimental IC(50) values at different time scales (0-1 to 0-10 ns). This study clearly demonstrates that the MM-PBSA based ΔG(Bind) (ΔG(Bind)-PB) values provide very good correlation with experimental IC(50) values (quantitative and qualitative) when MD simulation is carried out for a longer time; however, MM-GBSA based ΔG(Bind) (ΔG(Bind)-GB) values show acceptable correlation for shorter time of simulation also. The accuracy of ΔG(Bind)-PB increases and ΔG(Bind)-GB remains almost constant with the increasing time of simulation.

MIA-QSAR Modeling of the Anti-HIV-1 Protease Activities and Cytotoxicities of Ritonavir Analogs

Drug-likeness and toxicity prediction of compounds are so important as to estimate their bioactivities. In rational design of drugs, looking for safe rather than only highly active synthetic targets has increasingly became mandatory. In this context, structure-based methods to model toxicities of drug-like compounds arise as fundamental tasks to achieve safer drugs. Accordingly, the MIA-QSAR method, which has been widely applied to model bioactivities of several classes of compounds, can also be used to predict toxicities of drug-like compounds. In fact, the MIA-based approach has shown to be accurate to model bioactivities, boiling points, NMR chemical shifts and electrophoretic profiles, but it has been used to model cytotoxicities for the first time in this work, in order to contribute for studies to develop safer drugs. The QSAR modeling of bioactivities (pEC50) and cytotoxicities (CCIC50) of a series of HIV-1 protease inhibitors, some ritonavir derivatives, is reported in this work using the MIA-QSAR approach. The statistical quality of both models indicates that pEC50 and CCIC50 of ritonavir analogs can be reliably predicted using this method; therefore, improved drugs can be designed.

Enamino-oxindole HIV protease inhibitors

We have designed and synthesized a series of HIV protease inhibitors (PIs) with enamino-oxindole substituents optimized to interact with the S2′ subsite of the HIV protease binding pocket. Several of these inhibitors have sub-nanomolar Ki and antiviral IC50 in the low nM range against WT HIV and against a panel of multi-drug resistant (MDR) strains.

Efficient calculation of molecular configurational entropies using an information theoretic approximation.

Accurate computation of free energy changes upon molecular binding remains a challenging problem, and changes in configurational entropy are especially difficult due to the potentially large numbers of local minima, anharmonicity, and high-order coupling among degrees of freedom. Here we propose a new method to compute molecular entropies based on the maximum information spanning tree (MIST) approximation that we have previously developed. Estimates of high-order couplings using only low-order terms provide excellent convergence properties, and the theory is also guaranteed to bound the entropy. The theory is presented together with applications to the calculation of the entropies of a variety of small molecules and the binding entropy change for a series of HIV protease inhibitors. The MIST framework developed here is demonstrated to compare favorably with results computed using the related mutual information expansion (MIE) approach, and an analysis of similarities between the methods is presented.

Synthesis and activity of new acylated diaminohydroxyalkanes as human immunodeficiency virus protease inhibitors.

A series of HIV-1 protease inhibitors based on the lead compound Pc (IC50 = 165 nmol/l) with structural modifications at P1/P1' substituents or with a lengthening at its core unit were synthesized from amino acid starting materials. All analogues were less active than Pc against the protease.

P1-Substituted Symmetry-Based Human Immunodeficiency Virus Protease Inhibitors with Potent Antiviral Activity against Drug-Resistant Viruses

Because there is currently no cure for HIV infection, patients must remain on long-term drug therapy, leading to concerns over potential drug side effects and the emergence of drug resistance. For this reason, new and safe antiretroviral agents with improved potency against drug-resistant strains of HIV are needed. A series of HIV protease inhibitors (PIs) with potent activity against both wild-type (WT) virus and drug-resistant strains of HIV was designed and synthesized. The incorporation of substituents with hydrogen bond donor and acceptor groups at the P1 position of our symmetry-based inhibitor series resulted in significant potency improvements against the resistant mutants. By this approach, several compounds, such as 13, 24, and 29, were identified that demonstrated similar or improved potencies compared to 1 against highly mutated strains of HIV derived from patients who previously failed HIV PI therapy. Overall, compound 13 demonstrated the best balance of potency against drug resistant strains of HIV and oral bioavailability in pharmacokinetic studies. X-ray analysis of an HIV PI with an improved resistance profile bound to WT HIV protease is also reported.

Location, Location, Location

Location, Location, Location

Modeling of novel HIV-1 protease inhibitors incorporating N-Aryl-oxazolidinone-5-carboxamides as P2 ligands using quantum chemical and topological finger print descriptors

This article presents two QSAR studies on the novel series of HIV-1 protease inhibitors incorporating N-phenyloxazolidinone-5-carboxamides into the (hydroxyethylamino) sulfonamide scaffold as P2 ligands. All the statistical calculations have been done using PRECLAV software. A heuristic algorithm selects the best multiple linear regression (MLR) equation according to the highest leave-one-out cross-validation correlation coefficient. In the first QSAR study, only the Quantum Chemical descriptors have been used. The correlation between the observed values and the calculated values of activity is good (r2 = 0.935, Se = 0.3782, r2cv = 0.900, F = 76.6568). The second QSAR study has used both quantum chemical descriptors and topological finger print descriptors. The correlation between the observed values and the calculated values of activity is very good (r2 = 0.9638, Se = 0.2823, r2cv = 0.9492, F = 141.8338). The virtual molecular fragments that lead to a significant increase of the inhibitor activity are CH3 and CH. The virtual fragments C4H3S and C6H2 lead to significant decreases in the inhibitory activity. The results are critically discussed using Ridge statistics.

Epsilon substituted lysinol derivatives as HIV-1 protease inhibitors

A series of HIV-1 protease inhibitors containing an epsilon substituted lysinol backbone was synthesized. Two novel synthetic routes using N-boc-l-glutamic acid alpha-benzyl ester and 2,6-diaminopimelic acid were developed. Incorporation of this epsilon substituent enabled access to the S2 pocket of the enzyme, affording high potency inhibitors. Modeling studies and synthetic efforts suggest the potency increase is due to both conformational bias and van der Waals interactions with the S2 pocket.

Synthesis and biological evaluation of novel allophenylnorstatine-based HIV-1 protease inhibitors incorporating high affinity P2-ligands

A series of stereochemically defined cyclic ethers as P2-ligands were incorporated in an allophenylnorstatine-based isostere to provide a new series of HIV-1 protease inhibitors. Inhibitors 3b and 3c, containing conformationally constrained cyclic ethers, displayed impressive enzymatic and antiviral properties and represent promising lead compounds for further optimization.

HIV-1 Protease Inhibitors with a Transition-State Mimic Comprising a Tertiary Alcohol: Improved Antiviral Activity in Cells

By a small modification in the core structure of the previously reported series of HIV-1 protease inhibitors that encompasses a tertiary alcohol as part of the transition-state mimicking scaffold, up to 56 times more potent compounds were obtained exhibiting EC(50) values down to 3 nM. Three of the inhibitors also displayed excellent activity against selected resistant isolates of HIV-1. The synthesis of 25 new and optically pure HIV-1 protease inhibitors is reported, along with methods for elongation of the inhibitor P1' side chain using microwave-accelerated, palladium-catalyzed cross-coupling reactions, the biological evaluation, and X-ray data obtained from one of the most potent analogues cocrystallized with both the wild type and the L63P, V82T, I84 V mutant of the HIV-1 protease.

Synthesis of novel HIV protease inhibitors (PI) with activity against PI-resistant virus

A series of HIV protease inhibitors with modifications on the P3 position have been designed and synthesized. These compounds exhibit excellent antiviral activity against both the wild type enzyme and PI-resistant clinical viral isolates. The synthesis and biological activity of the compounds are described.