HIV-1 PR Inhibitors Research Articles

Combating HTLV-1 infections with Taxus baccata phytoconstituents: Molecular mechanisms potential anti-ATLL agents

Taxus baccata is recognized as a traditional herb with antiviral and anticancer properties, making it a valuable candidate for anti-proliferative and antiviral agents, particularly in the absence of a cure for HTLV-1 infection and related diseases. The alkaloid extract of Taxus baccata was evaluated for its impact on HTLV-1-MT2 cell proliferation and HTLV-1 protease activity, presenting a promising avenue for therapeutic applications akin to HIV-PR inhibitors. Given the pressing need for effective treatments for HTLV-1-associated conditions, our study delved into the alkaloid extract's effects through immunofluorescence assays on HTLV-1 protease both in vitro and in silico. Confirmation of Taxus baccata extraction was achieved through immunofluorescence, infrared spectroscopy (IR), gas chromatography-mass spectrometry (GC-MS), and high-performance liquid chromatography (HPLC) analysis, with paclitaxel serving as a control. Furthermore, the anticancer properties of the alcoholic and alkaloid extracts were explored through in vitro assays using various cell lines, including HTLV-1-MT2, A549, HT29, and MCF7, alongside flow cytometry assessments. Notably, treatment with the alkaloid extract significantly impacted the survival of HTLV-1-MT2 cells (-2.44±0.012), alcoholic extract (11.17±0.13) and paclitaxel (0.00±0.18) were evaluated. GC-MS analysis identified Dimethyl malate, Lichexanthone, and Glycinexylidide as bioactive compounds within the plant, with investigations into their molecular interactions with HTLV-1 protease conducted. Molecular dynamics studies revealed key interaction sites between the compounds and HTLV-1 protease (PDB ID:4YDF), particularly highlighting the binding sequence of the dimethyl malate ligand within the protease A chain (Ala59). Collectively, the alkaloid compounds from Taxus baccata exhibit potential inhibitory effects on HTLV-1 oncovirus proliferation and transmission.

Synthesis and evaluation of nitrogen-containing derivatives of 3,11-dioxo-olean-12-en-30-oic acid against HIV-1 protease

Thirteen nitrogen-containing derivatives of 3,11-dioxo-olean-12-en-30-oic acid were synthesised by introducing various amino acids and nitrogen-containing heterocyclic groups at the 30-carboxyl group, starting from 18β-glycyrrhetinic acid. Among the 13 derivatives, 10 exhibited inhibitory activity against HIV-1 PR, with IC50 values ranging from 0.19 to 0.94 mM. Notably, derivatives 2, 3 and 5 displayed relatively moderate inhibitory activity, with IC50 values below 0.24 mM. Molecular docking studies provided further insights into the interaction between derivatives (2, 3 and 5) and the active sites of HIV-1 PR. The results revealed favourable hydrophobic-hydrophobic and hydrogen bonding interactions, with docking scores ranging from −6.22 to −7.00 and glide emodel values from −62.9 to −48.6 (kcal/mol). These findings underscore the potential of derivatives 2, 3 and 5 as promising candidates for the development of HIV-1 PR inhibitors.

A multi-layer photonic spiking neural network with a modified backpropagation algorithm for nonlinear classification

In this work, we construct a fully connected multi-layer photonic spiking neural network (PSNN) based on excitable vertical-cavity surface-emitting lasers with an embedded saturable absorber (VCSELs-SA) equipped with the modified supervised backpropagation (BP) algorithm. Different from the traditional BP algorithm, our proposed modified BP algorithm is based on optical spikes, and its activation function exploits the excitable characteristic of VCSELs-SA. It is demonstrated that this BP PSNN can be competent in linearly inseparable problems by correctly solving the exclusive or (XOR) problem. Thus, a three-layer fully connected BP PSNN is designed to perform the prediction of Human immunodeficiency virus-1 protease (HIV-1 PR) cleavage sites and achieves 91.95% classification accuracy with the modified BP algorithm, which could be a useful tool in helping to find effective inhibitors of HIV PR to fight against acquired immunodeficiency syndrome (AIDS). These results demonstrate the validity of our modified BP algorithm in dealing with nonlinear classification problems in PSNNs, which is helpful for supervised learning in the photonic neuromorphic computing architecture for future neuromorphic applications.

Evaluation of novel HIV-1 protease inhibitors with DRV-resistance by utilizing 3D-QSAR molecular docking and molecular dynamics simulation

Molecular dynamics simulations were performed to explore the interaction mode of DRV derivatives binding to target proteins and to identify new potential HIV-1 PR inhibitors with stronger activity.

The design of bioactive marine peptides as a HIV-1 protease inhibitor

Background: Human immunodeficiency virus/acquired immunodeficiency syndrome (HIV or AIDS) is a disease related to the human immune system. Given its important role in viral replication, HIV1 protease (HIV1 PR) becomes the major therapeutic target in the treatment of AIDS. In this case, we need a dynamic aspect of molecular interactions that can demonstrate the important role of conformational variability in the design of HIV1 PR inhibitors. There are several inhibitor candidates from marine organisms, such as the LLEYSL and LLEYSI bioactive peptides produced by oysters (Crassostrea gigas). Objective: Proteinpeptide docking method was used in silico to identify, evaluate, and explore the molecular interactions between bioactive peptide molecules and HIV-1 protease macromolecules. Methods: The sequencing of bioactive peptide molecules was modeled into 3D conformation using the PEPFOLD software. The best conformation was chosen for the study of molecular interactions against HIV1 protease macromolecules using the PatchDock software. The molecular interactions formed were further observed using the BIOVIA Discovery Studio 2020 software. Results: The results of this study indicated that the LLEYSL bioactive peptide had the best affinity with an ACE score of minus 1284.70 kJ per mol. Conclusion: Bioactive peptide molecule is predicted to be a candidate for HIV1 protease inhibitor. Keywords: AIDS, HIV1 protease, bioactive peptides, protein-peptide docking, in silico

The Pseudo-Symmetric N-benzyl Hydroxyethylamine Core in a New Series of Heteroarylcarboxyamide HIV-1 Pr Inhibitors: Synthesis, Molecular Modeling and Biological Evaluation.

Here, we report the synthesis, enzyme inhibition and structure–activity relationship studies of a new potent class of HIV-1 protease inhibitors, which contain a pseudo-symmetric hydroxyethylamine core and heteroarylcarboxyamide moieties. The simple synthetic pathway furnished nine compounds in a few steps with high yields. The compounds were designed taking into account our previous results on other series of inhibitors with different substituents at P’ and P’’ and different ways of linking them to the inhibitor core. Potent inhibitory activity was obtained with nanomolar IC50 values measured with a standard fluorimetric test in 100 mM MES buffer, pH 5.5, containing 400 mM NaCl, 1 mM EDTA, 1 mM DTT and 1 mg/ml BSA. Compounds 9a–c, containing the indole ring in P1, exhibited an HIV-1 protease inhibitory activity more powerful than darunavir in the same assay. To obtain molecular insight into the binding properties of these compounds, docking analysis was performed, and their binding properties were also compared.

An insight to the molecular interactions of the FDA approved HIVPR drugs against L38L↑N↑L PR mutant.

The aspartate protease of the human immune deficiency type-1 virus (HIV-1) has become a crucial antiviral target in which many useful antiretroviral inhibitors have been developed. However, it seems the emergence of new HIV-1 PR mutations enhances drug resistance, hence, the available FDA approved drugs show less activity towards the protease. A mutation and insertion designated L38L↑N↑L PR was recently reported from subtype of C-SA HIV-1. An integrated two-layered ONIOM (QM:MM) method was employed in this study to examine the binding affinities of the nine HIV PR inhibitors against this mutant. The computed binding free energies as well as experimental data revealed a reduced inhibitory activity towards the L38L↑N↑L PR in comparison with subtype C-SA HIV-1 PR. This observation suggests that the insertion and mutations significantly affect the binding affinities or characteristics of the HIV PIs and/or parent PR. The same trend for the computational binding free energies was observed for eight of the nine inhibitors with respect to the experimental binding free energies. The outcome of this study shows that ONIOM method can be used as a reliable computational approach to rationalize lead compounds against specific targets. The nature of the intermolecular interactions in terms of the host-guest hydrogen bondinteractions is discussed using the atoms in molecules (AIM)analysis. Natural bond orbital analysis was also used to determine the extent of charge transfer between the QM region of the L38L↑N↑L PR enzyme and FDA approved drugs. AIM analysis showed that the interaction between the QM region of the L38L↑N↑L PR and FDA approved drugs are electrostatic dominant, the bond stability computed from the NBO analysis supports the results from the AIM application. Future studies will focus on the improvement of the computational model by considering explicit water molecules in the active pocket. We believe that this approach has the potential to provide information that will aid in the design of much improved HIV-1 PR antiviral drugs.

Investigation of the binding free energies of FDA approved drugs against subtype B and C-SA HIV PR: ONIOM approach

Human immune virus subtype C is the most widely spread HIV subtype in Sub-Sahara Africa and South Africa. A profound structural insight on finding potential lead compounds is therefore necessary for drug discovery. The focus of this study is to rationalize the nine Food and Drugs Administration (FDA) HIV antiviral drugs complexed to subtype B and C-SA PR using ONIOM approach. To achieve this, an integrated two-layered ONIOM model was used to optimize the geometrics of the FDA approved HIV-1 PR inhibitors for subtype B. In our hybrid ONIOM model, the HIV-1 PR inhibitors as well as the ASP 25/25' catalytic active residues were treated at high level quantum mechanics (QM) theory using B3LYP/6-31G(d), and the remaining HIV PR residues were considered using the AMBER force field. The experimental binding energies of the PR inhibitors were compared to the ONIOM calculated results. The theoretical binding free energies (?Gbind) for subtype B follow a similar trend to the experimental results, with one exemption. The computational model was less suitable for C-SA PR. Analysis of the results provided valuable information about the shortcomings of this approach. Future studies will focus on the improvement of the computational model by considering explicit water molecules in the active pocket. We believe that this approach has the potential to provide much improved binding energies for complex enzyme drug interactions.

2D-QSAR study of fullerene nanostructure derivatives as potent HIV-1 protease inhibitors

The protease of human immunodeficiency virus1 (HIV-PR) is an essential enzyme for antiviral treatments. Carbon nanostructures of fullerene derivatives, have nanoscale dimension with a diameter comparable to the diameter of the active site of HIV-PR which would in turn inhibit HIV. In this research, two dimensional quantitative structure-activity relationships (2D-QSAR) of fullerene derivatives against HIV-PR activity were employed as a powerful tool for elucidation the relationships between structure and experimental observations. QSAR study of 49 fullerene derivatives was performed by employing stepwise-MLR, GAPLS-MLR, and PCA-MLR models for variable (descriptor) selection and model construction. QSAR models were obtained with higher ability to predict the activity of the fullerene derivatives against HIV-PR by a correlation coefficient (R2training) of 0.942, 0.89, and 0.87 as well as R2test values of 0.791, 0.67and 0.674 for stepwise-MLR, GAPLS-MLR, and PCA -MLR models, respectively. Leave-one-out cross-validated correlation coefficient (R2CV) and Y-randomization methods confirmed the models robustness. The descriptors indicated that the HIV-PR inhibition depends on the van der Waals volumes, polarizability, bond order between two atoms and electronegativities of fullerenes derivatives. 2D-QSAR simulation without needing receptor's active site geometry, resulted in useful descriptors mainly denoting “C60 backbone-functional groups” and “C60 functional groups” properties. Both properties in fullerene refer to the ligand fitness and improvement van der Waals interactions with HIV-PR active site. Therefore, the QSAR models can be used in the search for novel HIV-PR inhibitors based on fullerene derivatives.

New 1(2H)-phthalazinone derivatives as potent nonpeptidic HIV-1 protease inhibitors: molecular docking studies, molecular dynamics simulation, oral bioavailability and ADME prediction

Molecular docking simulations of compounds 1–7, the newly synthesised 1(2H)-phthalazinone derivatives with N-(dimethylamino)ethyl pendant arm, as potent inhibitors of HIV-1 protease (HIV-1 PR) were performed. The results of calculations show that compounds 1–7 can form stable complexes with HIV-1 PR and their inhibitory action is mainly based on combination of intermolecular hydrogen bonds and ionic interactions between flexible cationic ammonium moiety of ligands and deprotonated carboxylic residues Asp25 and Asp29 of the target receptor. Molecular dynamics calculation in explicit water environment of the best ranked complex of compound 3 with HIV-1 PR reveals its high stability with conservation of strong salt bridge interactions during all simulation time. Per-residue decomposition of the binding free energy of HIV-1 PR complex with compound 3 calculated with the MM-PBSA method shows electrostatic and van der Waals interactions as the main favourable components. Estimated oral bioavailability and calculated absorption, distribution, metabolism and excretion (ADME) descriptors, namely, intestinal absorption, aqueous solubility and blood–brain barrier penetration, for compounds 1–7 indicate their good pharmacokinetic profile in humans after oral administration. Enthalpically favourable contribution of ligand–receptor salt bridge interactions and hydrogen bonds to binding free energy in calculated complexes of compounds 1–7 with HIV-1 PR also suggests a potent feature to combat a drug resistance to HIV-1 PR inhibitors.

Radial basis function neural networks based on the projection pursuit and principal component analysis approaches: QSAR analysis of fullerene[C60]-based HIV-1 PR inhibitors

In this work, projection pursuit (PP) and principal component analysis (PCA) are combined with radial basis function networks (RBFNs) to perform the quantitative structure–activity relationship (QSAR) studies on the binding affinities (pEC50, i.e., minus decimal logarithm of the 50 % effective concentration) of 47 fullerene derivatives as inhibitors of the human immunodeficiency virus type 1 protease. RBFN is applied to construct the nonlinear QSAR models. The input of RBFN is the scores of PP or PCA, and genetic algorithm is used to select the centers of RBFN. The methods are called PP-GA-RBF and PCA-GA-RBF, respectively. The aim is the performance comparison of the proposed methods. To evaluate the performance of the methods, various statistical parameters such as \( Q_{F2}^{2} \) and \( r_{m}^{2} \) are calculated. The results demonstrated that the predictive performance of the proposed PP-GA-RBF is better than PCA-GA-RBF and previous studies. The applicability domain of the models is assessed by leverage and distance approaches.

Docking analysis of gallic acid derivatives as HIV-1 protease inhibitors.

HIV-1 Protease (HIV-1 PR) enzymes are essential for accurate assembly and maturation of infectious HIV retroviruses. The significant role of HIV-1 protease in viral replication has made it a potential drug target. In the recent past, phytochemical Gallic Acid (GA) derivatives have been screened for protease inhibitor activity. The present work aims to design and evaluate potential GA-based HIV-1 PR phytoinhibitors by docking approach. The ligands were prepared by ChemDraw and docking was performed in HEX software. In this present study, one of the GA analogues (GA4) emerged as a potent drug candidate for HIV-1 PR inhibition, and docking results showed it to be comparable with anti-HIV drugs, darunavir and amprenavir. The GA4 derivative provided a lead for designing more effective HIV-1 PR inhibitors.

Antimalarial activity of HIV-1 protease inhibitor in chromone series

Increasing parasite resistance to nearly all available antimalarial drugs becomes a serious problem to human health and necessitates the need to continue the search for new effective drugs. Recent studies have shown that clinically utilized HIV-1 protease (HIV-1 PR) inhibitors can inhibit the in vitro and in vivo growth of Plasmodium falciparum. In this study, a series of chromone derivatives possessing HIV-1 PR inhibitory activity has been tested for antimalarial activity against P. falciparum (K1 multi-drug resistant strain). Chromone 15, the potent HIV-1 PR inhibitor (IC50=0.65μM), was found to be the most potent antimalarial compound with IC50=0.95μM while primaquine and tafenoquine showed IC50=2.41 and 1.95μM, respectively. Molecular docking study of chromone compounds against plasmepsin II, an aspartic protease enzyme important in hemoglobin degradation, revealed that chromone 15 exhibited the higher binding affinity (binding energy=−13.24kcal/mol) than the known PM II inhibitors. Thus, HIV-1 PR inhibitor in chromone series has the potential to be a new class of antimalarial agent.

Structural basis for HTLV-1 protease inhibition by the HIV-1 protease inhibitor indinavir.

HTLV-1 protease (HTLV-1 PR) is an aspartic protease which represents a promising drug target for the discovery of novel anti-HTLV-1 drugs. The X-ray structure of HTLV-1 PR in complex with the well-known and approved HIV-1 PR inhibitor Indinavir was determined at 2.40 Å resolution. In this contribution, we describe the first crystal structure in complex with a nonpeptidic inhibitor that accounts for rationalizing the rather moderate affinity of Indinavir against HTLV-1 PR and provides the basis for further structure-guided optimization strategies.

Molecular modeling studies and comparative analysis on structurally similar HTLV and HIV protease using HIV-PR inhibitors

Retroviruses are most perilous viral family, which cause much damage to the Homo sapiens. HTLV-1 mechanism found to more similar with HIV-1 and both retroviruses are causative agents of severe and fatal diseases including adult T-cell leukemia (ATL) and the acquired immune deficiency syndrome (AIDS). Both viruses code for a protease (PR) that is essential for replication and therefore represents a key target for drugs interfering with viral infection. In this work, the comparative study of HIV-1 and HTLV-1 PR enzymes through sequence and structural analysis is reported along with approved drugs of HIV-PR. Conformation of each HIV PR drugs have been examined with different parameters of interactions and energy scorings parameters. MD simulations with respect to timescale event of 20 ns favors that, few HIV-PR inhibitors can be more active inside the HTLV-1 PR binding pocket. Overall results suggest that, some of HIV inhibitors like Tipranavir, Indinavir, Darunavir and Amprenavir are having good energy levels with HTLV-1. Due to absence of interactions with MET37, here we report that derivatives of these compounds can be much better inhibitors for targeting HTLV-1 proteolytic activity.

Molecular docking studies of chromone derivatives against wild type and mutant strains of HIV-1 protease

Developing a new HIV-1 protease (HIV-1 PR) inhibitor is still a challenging task to overcome the drug resistance mutations in the HIV-PR. In this study, docking simulations of chromone derivatives against wild type and eleven mutant variants HIV-1 PR were investigated using GOLD and Autodock programs. From both GOLD and Autodock results, chromone 3, the experimentally observed highly potent HIV-1 PR inhibitor, showed stronger binding affinity against every studied mutant strain (2AVS, 2AVO, 2AVV, 1MES, 1MET, 1MEU, 1SDU, 1SDV, 1C6Y, 2F8O, and 1SH9) than the wild-type enzyme (1AJX). Chromone 32, another potent inhibitor as well as chromones 33, 34, 37, and 47 also showed high binding interaction with several mutant-type enzymes. The coherent picture of the interactions at the active sites of mutant PR should facilitate the further design and development of new potent inhibitor against multidrug-resistant virus.

195 In silico study on HIV-PRIs substructures to terminate proteolytic activity in HTLV

Human T-lymphotropic virus (HTLV) is RNA retrovirus, which causes CD3 + and CD4 + T-cell type leukemia and demyelinating diseases, like tropical spastic myelopathy. The replicative stage of the virus is one of the critical stages for the development of the disease. At present, there are no approved therapeutic agents targeting HTLV. The HTLV mechanism of malignant cell growth in adult T-cell leukemia (ATL)/lymphoma, and the HTLV-PR has been an attractive target for anticancer drug design. In comparison with other retroviruses, HTLV also encodes protease (PR) enzyme which is essential for maturation. Both the HIV and HTLV proteases show high structural similarity but known inhibitors of HIV-PR are not able to inhibit the HTLV-PR, while comparing the binding pocket of both proteases, MET37 of HTLV shows repulsive role with known HIV inhibitors. Functional analysis of M37A mutation clearly shows that MET37 is highly important for the protease function. Available inhibitors were tested against the HTLV-PR binding pocket and failed to interact with MET37. Screening of similar libraries of known compounds provides better interactions with MET37 and further validation with in vivo and in vitro studies on these screened compounds will provide more strength in discovering potent inhibitor for HTLV-PR.

English

HIV-1 protease (HIV PR) is an essential enzyme needed in the proper assembly and maturation of infectious virions. HIV PR catalyses proteolytic cleavage of the polypeptide precursors into mature enzymes and structural proteins which is a critical step in the life cycle of HIV. The necessity of this enzyme in the virus life cycle makes it a promising target for therapy of the HIV infection. In order to dis- cover potential inhibitors of HIV PR, structure based virtual screening was performed using crystal structure of the protein obtained from PDB (2BB9). 46 Quinoxaline analogues were docked with 2BB9 and the highly interacting compounds based on their binding energies are reported here.

Development of QSAR models for predicting anti-HIV-1 activity using the Monte Carlo method

Abstract Abstract The CORAL software (http://www.insilico.eu/coral/) has been examined as a tool for modeling anti-HIV-1 activity by quantitative structure — activity relationships (QSAR) for three different sets: (i) TIBO derivatives (n=82) (ii) anti-HIV-1 activity of 2-amino-6-arylsulfonylbenzonitriles and their congeners (n=64), and (iii) the measured binding affinity for fullerene-based HIV-1 PR inhibitors (n=48). A new global invariant ATOMPAIR of the molecular structure which can be calculated with the simplified molecular input line entry system (SMILES) was studied. The ATOMPAIR is an indicator of the joint presence of pairs of chemical elements (F, Cl, Br, N, O, S, and P) and three types of bonds (double covalent bond, triple covalent bond, and stereo chemical bond). Six random splits into sub-training, calibration, and test set were examined for each set. For the three aforementioned sets, the use of ATOMPAIR in the modeling process improves the predictive potential of the models for six random splits. Graphical abstract

Dual Inhibitors for Aspartic Proteases HIV-1 PR and Renin: Advancements in AIDS–Hypertension–Diabetes Linkage via Molecular Dynamics, Inhibition Assays, and Binding Free Energy Calculations

Human immunodeficiency virus type 1 protease (HIV-1 PR) and renin are primary targets toward AIDS and hypertension therapies, respectively. Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) free-energy calculations and inhibition assays for canagliflozin, an antidiabetic agent verified its effective binding to both proteins (ΔG(pred) = -9.1 kcal mol(-1) for canagliflozin-renin; K(i,exp)= 628 nM for canagliflozin-HIV-1 PR). Moreover, drugs aliskiren (a renin inhibitor) and darunavir (an HIV-1 PR inhibitor) showed high affinity for HIV-1 PR (K(i,exp)= 76.5 nM) and renin (K(i,pred)= 261 nM), respectively. Importantly, a high correlation was observed between experimental and predicted binding energies (r(2) = 0.92). This study suggests that canagliflozin, aliskiren, and darunavir may induce profound effects toward dual HIV-1 PR and renin inhibition. Since patients on highly active antiretroviral therapy (HAART) have a high risk of developing hypertension and diabetes, aliskiren-based or canagliflozin-based drug design against HIV-1 PR may eliminate these side-effects and also facilitate AIDS therapy.