QSAR Studies Research Articles

Discovery of novel ALK2 inhibitors of pyrazolo-pyrimidines: A computational study

ALK2 is a serine/threonine kinase, involved in different signaling pathways and associated with cell proliferation and differentiation. The present study includes development of pharmacophore, 3-D QSAR, docking and virtual screening studies on 30 different pyrazolo[1,5-a]pyrimidine derivatives. The pharmacophore study provides ARRR_2 hypothesis with four different features essential for ALK2 kinase inhibitory activity. The 3 D-QSAR study determined the statistically significant model by using partial least-square regression (PLS) method with R 2 value of 0.9711 and Q 2 value of 0.6846. Validation of 3 D-QSAR has been performed by LOO cross-validation method where with R2CV value of 0.56. The virtual screening study on ZINC database provides compounds such as ZINC66091638, ZINC43524105, ZINC19458227 and ZINC72441013 involved good binding interactions (docking scores −8.91, −7.40, −8.43, and −9.47, respectively) with ALK2 kinase (PDB ID: 3Q4U). The docking study of pyrazolo-pyrimidines derivatives found potent compounds, 7i, 13r, 13d, and 21 with docking scores −9.83, −9.75, −9.76, and −9.75, respectively. The important interactions with amino acid residues were HID 286, ASN341. ADME properties further assist to provide important structural features of ALK2 kinase. The present study may be help to medicinal scientists in the direction to develop potent inhibitors against ALK2 kinase. Communicated by Ramaswamy H. Sarma

A computational estimation for alkyl chain effect in Schiff base pyridinium fluoride ionic liquid on chemical reactivity, thermophysical properties, pharmacokinetics, and biological activity by DFT approach

Amphiphilic pyridinium fluoride is the novel class of ionic liquid for drug discover for their biological and pharmacological activity. In this case, amphiphilic pyridinium cation was selected to this study. Changing the alkyl chain length, the effect was estimated on thermophysical, chemical, and biological activity. Using density functional theory (DFT), thermophysical and HOMO, LUMO were optimized and calculated. From HOMO, LUMO, the ionization energy, electronegativity, softness, hardness, electrophilicity (ω), and chemical potential (μ) were calculated. The HOMO, LUMO, and HOMO-LUMO gap are near to-8.85, -0.85, and 8.0. From QSAR study, the value of the Log P is from +1.5 to +2.6 as hydrophobic nature. As is observed the pharmacokinetics data, the Lipinski rule, bioavailability score, leadlikeness, solubility, and LogP o/w were calculated.

QSAR and Ab Initio studies of quinolon-4(1H)-imine derivatives as antimalarial agents

Malaria is still the most dangerous disease threat in the world, including in Indonesia. In Indonesia, it is estimated that there are 20 million cases of malaria per year. Malaria resistance to conventional drugs requires the search for new antimalarial drugs. Molecular modeling can be a solution to these problems. An activity study of 22 quinolone-4 (1H) -imine derivatives as antimalarials was carried out using the QSAR Quantitative Structure-Activity Relationship method. The electronic and molecular descriptors were obtained from the Hartree-Fock HF / 6-31G ab initio calculation. The multiple linear regression (MLR) method was used to construct the QSAR model. The best QSAR models produced are: pEC50 = -4,177 + (37,902 x qC3) + (171,282 x qC8) + (9,061 x qC10) + (125,818 x qC11) + (-149,125 x qC17) + (191,623 x qC18), with statistical parameters, n = 22; r2 = 0,910; SEE = 0,171; Fhit/Ftab = 4,510 dan PRESS = 0,697. The best QSAR equation model can be used as a reference for designing and predicting the antimalarial activity of Quinolon-4 (1H) -imine derivatives which have higher activity than the previous one

The index of ideality of correlation: QSAR studies of hepatitis C virus NS3/4A protease inhibitors using SMILES descriptors

ABSTRACT Robust and reliable QSAR models were developed to predict half-maximal inhibitory concentration (IC50) values of hepatitis C virus NS3/4A protease inhibitors from the Monte Carlo technique. 524 HCV NS3/4A protease inhibitors were extracted from the scientific literature to create a reasonably large set. The models were developed using CORAL software by using two target functions namely target function 1 (TF1) without applying the index of ideality of correlation (IIC) and target function 2 (TF2) that uses IIC. The constructed models based on TF2 were statistically more significant and robust than the models based on TF1. The determination coefficients (r 2) of training and test sets were 0.86 and 0.88 for the best split based on TF2. The promoters of the increase/decrease of activity were also extracted and interpreted in detail. The model interpretation results explain the role of different structural attributes in predicting the pIC50 values of hepatitis C virus NS3/4A protease inhibitors. Based on the mechanistic model interpretation results, eight new compounds were designed and their pIC50 values were predicted based on the average prediction of ten models.

Molecular modeling, QSAR analysis and antimicrobial properties of Schiff base derivatives of isatin

• New isatin Schiff base derivatives have been synthesized as potent antimicrobial agents. • The compounds were docked at the active site of PDF enzyme (PDB ID: 1G2A ) to predict the possible mode of action of compounds. • Docking studies indicated the stable ligand-protein complexes formed by all compounds. • The TOPKAT protocol in DS 3.0 software showed lower toxicity of the designed isatin Schiff base derivatives. • Antimicrobial study and regression analysis have been done for all compounds. A new series of novel Schiff bases has been designed, synthesized and tested for in vitro antimicrobial activity. QSAR studies followed by antibacterial screening using broth dilution technique showed excellent MIC values against four human pathogens, namely Escherichia coli, Pseudomonas aeruginosa, Bacillus cerus and Staphylococcus aureus. A great synergistic effect was observed when the test compounds were used in combination with chloramphenicol and ciprofloxacin. The MIC of the combination was reduced up to 1/4 th or 1/32 nd of the original value, indicating thereby that the combination was 4 to 32 times more potent than the test compounds. Molecular modeling suggested that all ligands interacted well within the active site of peptide deformylase enzyme (PDF) (PDB ID: 1G2A ) and formed stable complexes. Antifungal screening of all compounds was also done using the food poisoning in vitro method on four plant pathogenic fungi, namely Fusarium oxysporum, Aspergillus flavus, Aspergillus niger and Alternaria brassicae. The compounds 8 and 10 showed good activity against F. oxysporum at 100 µg/mL with inhibitory index 70% and 82.5%, respectively and IC 50 value of 2.75 and 2.29 µg/mL, respectively. Better intestinal absorption, oral bioavailability and cell permeation have been predicted for the test compounds using ADMET protocol available within Discovery Studio 3.0 (DS 3.0). The study thus laid the foundation for the development of better antibacterial agents via a combination approach and safe agricultural fungicides.

Antiviral phytochemicals as potent inhibitors against NS3 protease of dengue virus

Dengue, a mosquito-borne disease, has appeared as a major infectious disease globally. The virus requires its proteins to replicate and reproduce in the host cell. The NS3 protease converts the polyprotein to functional proteins with the help of the NS2B cofactor. Thus, NS3 protease is a promising target to develop antiviral inhibitors against the dengue virus. A systematic screening including ADMET properties, molecular docking, molecular dynamics (MD) simulation, binding free energy calculation, and QSAR studies is carried out to predict potent inhibitors against the NS3 protease. From the screening of 40 antiviral phytochemicals, ADMET properties analysis was used to screen out ligands that violate ADME rules and have probable toxicity. Cyanidin 3-Glucoside, Dithymoquinone, and Glabridin were predicted to be potent inhibitors against the NS3 protease according to their binding affinity. These ligands showed several noncovalent interactions, including hydrogen bond, hydrophobic interaction, electrostatic interaction, pi-sulfur interactions. The ligand-protein complexes were further scrutinized using 250 ns molecular dynamics simulation. The MM-PBSA binding free energy calculation was conducted to investigate their binding stability in dynamic conditions. The calculated pIC50(mM) value was predicted using the QSAR model with 89.91% goodness of fit. The predicted biologocal activity value for the ligands indicates they might have good potency.

New isolate from Salvinia molesta with antioxidant and urease inhibitory activity.

Urease plays a significant role in the pathogenesis of urolithiasis pyelonephritis, urinary catheter encrustation, hepatic coma, hepatic encephalopathy, and peptic acid duodenal ulcers. Salvinia molesta was explored to identify new bioactive compounds with particular emphasis on urease inhibitors. The aqueous methanol extract was fractionated using solvents of increasing polarity. A series of column chromatography and later HPLC were performed on butanol extract. The structures of the resulting pure compounds were resolved using NMR (1D and 2D), infrared, and mass spectroscopy. The novel isolate was evaluated for antioxidant activity (using DPPH, superoxide anion radical scavenging, oxidative burst, and Fe+2 chelation assays), anti-glycation behavior, anticancer activity, carbonic anhydrase inhibition, phosphodiesterase inhibition, and urease inhibition. One new glucopyranose derivative 6'-O-(3,4-dihydroxybenzoyl)-4'-O-(4-hydroxybenzoyl)-α/β-D-glucopyranoside (1) and four known glycosides were identified. Glycoside 1 demonstrated promising antioxidant potential with IC50 values of 48.2 ± 0.3, 60.3 ± 0.6, and 42.1 ± 1.8μM against DPPH, superoxide radical, and oxidative burst, respectively. Its IC50 in the Jack bean urease inhibition assay was 99.1 ± 0.8μM. The mechanism-based kinetic studies presented that compound 1 is a mixed-type inhibitor of urease with a Ki value of 91.8 ± 0.1μM. Finally, molecular dynamic simulations exploring the binding mode of compound 1 with urease provided quantitative agreement between estimated binding free energies and the experimental results. The studies corroborate the use of compound 1 as a lead for QSAR studies as an antioxidant and urease inhibitor. Moreover, it needs to be further evaluated through the animal model, that is, in vivo or tissue culture-based ex-vivo studies, to establish their therapeutic potential against oxidative stress phosphodiesterase-II and urease-induced pathologies.

Performance of PLS, GA-PLS and OSC-GA-PLS Models in QSAR Study of Pyrazolone Derivatives Inhibitory Activity, and Image Processing for New Compounds Designing

Performance of PLS, GA-PLS and OSC-GA-PLS Models in QSAR Study of Pyrazolone Derivatives Inhibitory Activity, and Image Processing for New Compounds Designing

Synthesis, Biological Evaluation, and QSAR Studies of 3-Iodochromone Derivatives as Potential Fungicides.

Despite the emergence of novel biotechnological and biological solutions, agrochemicals continue to play an important role in crop protection. Fungicide resistance is becoming a major problem; numerous cases of fungicide resistance have occurred worldwide in the last decade, resulting in the loss of several fungicides. The discovery of new molecules has therefore assumed critical importance in crop protection. In our quest for biologically active molecules, we herein report the synthesis of a series of twenty-one 3-Iodochromone derivatives (4a–4u), in a two-step process by condensation of 2-hydroxyacetophenone derivatives (2a–2u) with N,N-dimethylformamidedimethylacetal yielding enaminones (3a–3u), followed by cyclization with iodine to corresponding 3-iodochromones. Characterization of these compounds was done by IR, 1H NMR, 13C NMR, and LC-HRMS techniques. All synthesized compounds were screened for their fungicidal activity against Sclerotium rolfsii. Among these 6,8-Dichloro-3-iodochromone 4r was found to be most active (ED50 = 8.43 mg L−1). 2D-Quantitative Structural Activity Relationship (2D-QSAR) analysis was also performed by generating three different models viz., Multiple Linear Regression (MLR, Model 1), Principal Component Regression (PCR, Model 2), and Partial Least Squares (PLS, Model 3). Predictive power and statistical significance of these models were assessed with external and internal validation and leave one-out cross-validation was used for verification. In QSAR study, MLR (Model 1) was found to be best having correlation coefficient (r2) 0.943, cross-validated correlation coefficient (q2) 0.911 and r2pred 0.837. It was observed that DeltaEpsilonC, T_2_Cl_6, T_2_F_6, T_T_F_3, and ZCompDipole are the major descriptors which influence the fungicidal activity of 3-Iodochromone derivatives. The physicochemical parameters were estimated by the VLifeMDS 4.6 software. The QSAR study results will be helpful for structure optimization to improve the activity.

Molecular Docking Q-SAR Studies of Benzimidazole as Antifungal Nucleus

Benzimidazole and its derivatives are used in organic synthesis and vermicides or fungicides as they inhibit the action of certain microorganisms. The molecules to be analysed were aligned on an appropriate template, which is considered to be common substructure. The protein structure of PDB name along with their inhibitor was retrieved from RCSB Protein Data Bank (PDB entry code: 6T1O). The protein structure were subjected to energy minimization and charge calculation (AMBER7FF99), docking score of compounds on 6T1O PDB describe the ligand interaction. Virtual library of benzimidazoles derivatives to find lead structures to test against C. albicans. Twenty compounds were designed in which heterocyclic ring is substituted at NH group of Substituted ortho-phenylenediamine moiety while some compound also bearing chloro and nitro group on para position of aromatic ring.

QSAR Study of a Serie of Benzimidazolylchalcone Derivatives by the Density Fonctional Theory (DFT) Method

This QSAR study involved a series of benzimidazolylchalcone derivatives. It allowed us to obtain a model from the molecular descriptors and anthelminthical activity against Haemonchus contortus. The molecular descriptors were obtained by applying the methods of quantum chemistry at the B3LYP/6-31G (d) level. The statistical indicators of the model are: the coefficient of determination R2 equals 0.990, the standard deviation S equals 0.209, the Fischer coefficient F equals 153.055 and the cross-validation coefficient equals 0.990. This model has good statistical performances. The quantum descriptors of dipole moment (μD) and electronic energy are responsible of the anthelminthic activity of benzimidazolylchalcone derivatives. In addition, the dipole moment is the priority descriptor for the prediction of the antibacterial activity of the studied compounds. The Eriksson et al. acceptance criteria used for the test set is verified. The values of the pCL100theo/pCL100exp ratio of the theoretical and experimental activities for the test set aim towards the unit.

Synthesis and Anti-Pancreatic Cancer Activity Studies of Novel 3-Amino-2-hydroxybenzofused 2-Phospha-γ-lactones.

A series of 3-amino-2-hydroxybenzofused 2-phosphalactones (4a–l) has been synthesized from the Kabachnik–Fields reaction via a facile route from a one-pot three-component reaction of diphenylphosphite with various 2-hydroxybenzaldehyes and heterocyclic amines in a new way of expansion. The in vitro anti-cell proliferation studies by MTT assay have revealed them as potential Panc-1, Miapaca-2, and BxPC-3 pancreatic cell growth inhibitors, and the same is supported by molecular docking, QSAR, and ADMET studies. The MTT assay of their SAHA derivatives against the same cell lines evidenced them as potential HDAC inhibitors and identified 4a, 4b, and 4k substituted with 1,3-thiazol, 1,3,4-thiadiazol, and 5-sulfanyl-1,3,4-thiadiazol moieties on phenyl and diethylamino phenyl rings as potential ones. Additionally, the flow cytometric analyses of 4a, 4b, and 4k against BxPC-3 cells revealed compound 4k as a lead compound that arrests the S phase cell cycle growth at low micromolar concentrations. The ADMET properties have ascertained their inherent pharmacokinetic potentiality, and the wholesome results prompted us to report it as the first study on anti-pancreatic cancer activity of cyclic α-aminophosphonates. Ultimately, this study serves as a good contribution to update the existing knowledge on the anticancer organophosphorus heterocyclic compounds and elevates the scope for generation of new anticancer drugs. Further, the studies like QSAR, drug properties, toxicity risks, and bioactivity scores predicted for them have ascertained the synthesized compounds as newer and potential drug candidates. Hence, this study had augmented the array of α-aminophosphonates by adding a new collection of 3-amino-2-hydroxybenzofused 2-phosphalactones, a class of cyclic α-aminophosphonates, to it, which proved them as potential anti-pancreatic cancer agents.

Vilazodone-Tacrine Hybrids as Potential Anti-Alzheimer Agents: QSAR, Molecular Docking, and Molecular Dynamic (MD) Simulation Studies

Alzheimer's disease (AD) is a type of functional impairment of the brain, which gently degrades the patients' mental potency. The goal pursued in this study is to introduce novel drug candidates as acetylcholinesterase (hAChEIs) and butyl cholinesterase (hBuChE) inhibitors in the treatment of AD. In this study, more than 100 Vilazodone-Tacrin hybrids have been designed to inhibit hAchE and hBuChE. A series of chemical methods such as multiple linear regression (MLR) and GA-PLS were used to create relationships between structural features in these compounds and their hAchE/ hBuChE inhibitory activity. Molecular docking studies against hAChE (PDB ID: 1ACJ) and hBuChE (PDB ID: 4BDS) indicates the important amino acids inside the active site cavity that are responsible of essential interactions were Gly441, Ser122, Trp84, Asp72, Tyr130, and Gly117 for hAChE and Glu197, Thr120, Gly121, Asn83, Tyr332, Trp430, Trp82 and Asp70 for hBuChE. The best regression equation was obtained from GA-PLS, which predicts 92% of variances. Molecular dynamic (MD) simulations were also studied. The reliability, accuracy, and predictability of the proposed QSAR models were evaluated. Finally, an in silico screening study was conducted, and some compounds were introduced as logical candidates as novel anti-Alzheimer agents.

Structure-activity relationships of dually-acting acetylcholinesterase inhibitors derived from tacrine on N-methyl-d-Aspartate receptors.

Tacrine is a classic drug whose efficacy against neurodegenerative diseases is still shrouded in mystery. It seems that besides its inhibitory effect on cholinesterases, the clinical benefit is co-determined by NMDAR-antagonizing activity. Our previous data showed that the direct inhibitory effect of tacrine, as well as its 7-methoxy derivative (7-MEOTA), is ensured via a "foot-in-the-door" open-channel blockage, and that interestingly both tacrine and 7-MEOTA are slightly more potent at the GluN1/GluN2A receptors when compared with the GluN1/GluN2B receptors. Here, we report that in a series of 30 novel tacrine derivatives, designed for assessment of structure-activity relationship, blocking efficacy differs among different compounds and receptors using electrophysiology with HEK293cells expressing the defined types of NMDARs. Selected compounds (4 and 5) potently inhibited both GluN1/GluN2A and GluN1/GluN2B receptors; other compounds (7 and 23) more effectively inhibited the GluN1/GluN2B receptors; or the GluN1/GluN2A receptors (21 and 28). QSAR study revealed statistically significant model for the data obtained for inhibition of GluN1/Glu2B at-60 mV expressed as IC50 values, and for relative inhibition of GluN1/Glu2A at+40mV caused by a concentration of 100μM. The models can be utilized for a ligand-based virtual screening to detect potential candidates for inhibition of GluN1/Glu2A and/or GluN1/Glu2B subtypes. Using invivo experiments in rats we observed that unlike MK-801, the tested novel compounds did not induce hyperlocomotion in open field, and also did not impair prepulse inhibition of startle response, suggesting minimal induction of psychotomimetic side effects. We conclude that tacrine derivatives are promising compounds since they are centrally available subtype-specific inhibitors of the NMDARs without detrimental behavioral side-effects.

Design and Synthesis of a Novel PLK1 Inhibitor Scaffold Using a Hybridized 3D-QSAR Model.

Polo-like kinase 1 (PLK1) plays an important role in cell cycle progression and proliferation in cancer cells. PLK1 also contributes to anticancer drug resistance and is a valuable target in anticancer therapeutics. To identify additional effective PLK1 inhibitors, we performed QSAR studies of two series of known PLK1 inhibitors and proposed a new structure based on a hybridized 3D-QSAR model. Given the hybridized 3D-QSAR models, we designed and synthesized 4-benzyloxy-1-(2-arylaminopyridin-4-yl)-1H-pyrazole-3-carboxamides, and we inspected its inhibitory activities to identify novel PLK1 inhibitors with decent potency and selectivity.

In silico local QSAR modeling of bioconcentration factor of organophosphate pesticides.

The persistent and accumulative nature of the pesticide of indiscriminate use emerged as ecotoxicological hazards. The bioconcentration factor (BCF) is one of the key elements for environmental assessments of the aquatic compartment. Limitations of prediction accuracy of global model facilitate the use of local predictive models in toxicity modeling of emerging compounds. The BCF data of diverse organophosphate (n = 55) was collected from the Pesticide Properties Database and used as a model data set in the present study to explore physicochemical properties and structural alert concerning BCF. The structures were downloaded from Pubchem, ChemSpider database. Two splitting techniques (biological sorting and structure-based) were used to divide the whole dataset into training and test set compounds. The QSAR study was carried out with two-dimensional descriptors (2D) calculated from PaDEL by applying genetic algorithm (GA) as chemometric tools using QSARINS software. The models were statistically robust enough both internally as well as externally (Q2: 0.709-0.722, Q2 Ext: 0.717-0.903, CCC: 0.857-0.880). Overall molecular mass, presence of fused, and heterocyclic ring with electron-withdrawing groups affect the BCF value. The developed models reflected extended applicability domain (AD) and reliable predictions than the reported models for the studied chemical class. Finally, predictions of unknown organophosphate pesticides and the toxic nature of unknown organophosphate pesticides were commented on. These findings may be useful for the scientific community in prioritizing high potential pesticides of organophosphate class.

6-amide-2-aryl benzoxazole/benzimidazole derivatives as VEFGR-2 inhibitors in two-and three-dimensional QSAR studies: topomer CoMFA and HQSAR

The vascular endothelial growth factor (VEGF) is the main target of tumor treatment. VEGFR-2 is the main functional receptor of VEGF, which is involved in the regulation of angiogenesis. Based on hologram quantitative structure activity relationships (HQSAR) and topomer comparative molecular field analysis (topomer CoMFA), the contribution of 6-amide-2-aryl benzoxazole/benzimidazole derivatives (VEGFR-2 kinase inhibitors) to these structures was discussed and the corresponding modification strategies were proposed. The most effective HQSAR and topomer CoMFA models are generated by using a training set of 33 compounds. In order to ensure the robustness of the model, the randomization test was used, and 11 compounds were selected as the test set. The results show that the q2 of cross-validation is 0.646/0.659, and the r2 of non-cross-validation is 0.871/0.867, respectively. The data show that both models are reliable. Topomer CoMFA’s steric/electrostatic contour and HQSAR’s atomic contribution map show the structural characteristics controlling its inhibition ability. In addition, molecular docking is also used to study the interaction between these drugs and large proteins, and the ligand pair is connected to the active site of VEGFR-2 kinase, revealing the possible biological active conformation. This study showed that there was a wide interaction between 6-amide-2-aryl benzoxazole/benzimidazole derivatives and Hrg136 and Tyr356 residues of VEGFR-2 kinase active site. Finally, we used ADMET properties and drug-like properties to predict the newly designed molecules, and the results showed that they meet the conditions for becoming drugs and are expected to become potential anti-VEGFR-2 inhibitors. This study can provide a theoretical reference for the synthesis of target products of VEGFR-2 inhibitors.

QSAR study of unsymmetrical aromatic disulfides as potent avian SARS-CoV main protease inhibitors using quantum chemical descriptors and statistical methods

In silico research was executed on forty unsymmetrical aromatic disulfide derivatives as inhibitors of the SARS Coronavirus (SARS-CoV-1). Density functional theory (DFT) calculation with B3LYP functional employing 6-311 ​+ ​G(d,p) basis set was used to calculate quantum chemical descriptors. Topological, physicochemical and thermodynamic parameters were calculated using ChemOffice software. The dataset was divided randomly into training and test sets consisting of 32 and 8 compounds, respectively. In attempt to explore the structural requirements for bioactives molecules with significant anti-SARS-CoV activity, we have built valid and robust statistics models using QSAR approach. Hundred linear pentavariate and quadrivariate models were established by changing training set compounds and further applied in test set to calculate predicted IC50 values of compounds. Both built models were individually validated internally as well as externally along with Y-Randomization according to the OECD principles for the validation of QSAR model and the model acceptance criteria of Golbraikh and Tropsha’s. Model 34 is chosen with higher values of R2, R2test and Q2cv (R2 ​= ​0.838, R2test ​= ​0.735, Q2cv ​= ​0.757).It is very important to notice that anti-SARS-CoV main protease of these compounds appear to be mainly governed by five descriptors, i.e. highest occupied molecular orbital energy (EHOMO), energy of molecular orbital below HOMO energy (EHOMO-1), Balaban index (BI), bond length between the two sulfur atoms (S1S2) and bond length between sulfur atom and benzene ring (S2Bnz). Here the possible action mechanism of these compounds was analyzed and discussed, in particular, important structural requirements for great SARS-CoV main protease inhibitor will be by substituting disulfides with smaller size electron withdrawing groups. Based on the best proposed QSAR model, some new compounds with higher SARS-CoV inhibitors activities have been designed. Further, in silico prediction studies on ADMET pharmacokinetics properties were conducted.

Dehydroacetic Acid-Phenylhydrazone as a Potential Inhibitor for Wild-Type HIV-1 Protease: Structural, DFT, Molecular Dynamics, 3D QSAR and ADMET Characteristics

Despite several studies towards anti-HIV therapy, HIV infections remain a challenge due to the resistivity of developed drugs. The emergence of new HIV-1 PR mutations has led to the drug resistance of the available FDA-approved drugs and lower activity towards the HIV protease. Based on this the molecular properties of 4-hydroxy-6-methyl-3-[(1E)-1-(2-phenylhydrazinylidene) ethyl]-2H-pyran-2-one (DHAA-PH) has been carried out using the hybrid Density Functional Theory (DFT) and Time-Dependent (TDFT) method at B3LYP/6-31+G(d,p) levels of theory. To substantiate the sensitivity of functional applied M06-2X/ 6-311++G(2d,2p) and mPWB1W/6-311++G(2d,2p) was used to calculate the geometric, IR, 1H NMR, and energy gap calculations.DFT calculations with M06-2X and mPWB1W were observed to agree with the experiment compared to B3LYP functional. The absorption spectra of DHAA-PH showed three distinct bands which were designated as S0 to S1, S0to S2, and S0 to S3 in order of increasing energy. The high intensity (oscillator strength) of S0 to S1 infers that the transition is quantum-mechanically allowed, while the low intensity of S0 to S2 and S0 to S3 transitions suggests quantum mechanically forbidden transitions. Molecular dynamics simulations revealed that the obtained MMGBSA binding energies are better compared to the experimentally reported binding energies for HIV-1 protease inhibitors. 3D QSAR and computational ADMET study were performed. Pharmacophore fragments of the compound were identified as well as the fragments determining its toxicity and metabolic properties. Based on the analysis of these fragments, the ways to further design promising HIV1-protease inhibitors were proposed.

Design and Synthesis of N-Substituted 3,4-Pyrroledicarboximides as Potential Anti-Inflammatory Agents.

In the present paper, we describe the biological activity of the newly designed and synthesized series N-substituted 3,4-pyrroledicarboximides 2a–2p. The compounds 2a–2p were obtained in good yields by one-pot, three-component condensation of pyrrolo[3,4-c]pyrrole scaffold (1a–c) with secondary amines and an excess of formaldehyde solution in C2H5OH. The structural properties of the compounds were characterized by 1H NMR, 13C NMR FT-IR, MS, and elemental analysis. Moreover, single crystal X-ray diffraction has been recorded for compound 2h. The colorimetric inhibitor screening assay was used to obtain their potencies to inhibit COX-1 and COX-2 enzymes. According to the results, all of the tested compounds inhibited the activity of COX-1 and COX-2. Theoretical modeling was also applied to describe the binding properties of compounds towards COX-1 and COX-2 cyclooxygenase isoform. The data were supported by QSAR study.