R1 Position Research Articles

Quantum mechanics and 3D-QSAR studies on thienopyridine analogues: inhibitors of IKKβ

Inhibitor of kappa B kinase subunit β (IKKβ) is a main regulator of nuclear factor kappa B (NF-κB) and has received considerable attention as an attractive therapeutic target for the treatment of lung cancer or other inflammatory disease. A group of diversified thienopyridine derivatives exhibited a wide range of biological activity was used to investigate its structural requirements by using DFT and 3D-Quantitative structure activity relationship. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were established using the experimental activity of thienopyridine derivatives. The cross-validation coefficient (q2) values for CoMFA and CoMSIA are 0.671 and 0.647 respectively, were achieved, demonstrating high predictive capability of the model. The contour analysis indicate that presence of hydrophobic and electrostatic field is highly desirable for biological activity. The results indicate that substitution of hydrophobic group with electron withdrawing effect at R4 and R6 position have more possibility to increase the biological activity of thienopyridine derivatives. Subsequently molecular docking and DFT calculation were performed to assess the potency of the compounds.

Design of New Therapeutic Agents Targeting FLT3 Receptor Tyrosine Kinase Using Molecular Docking and 3D-QSAR Approach

Background: FMS-like tyrosine kinase-3 (FLT3) belongs to the class III Receptor Tyrosine Kinase (RTK) family. FLT3 is involved in normal hematopoiesis and is generally expressed in early hematopoietic progenitor cells. Mutations either with an internal tandem duplication of FMS-like tyrosine kinase-3 (FLT3-ITD) or point mutation at the activation loop leads to the Acute Myeloid Leukemia (AML), a highly heterogeneous disease. Thus, FLT3 is an important therapeutic target for AML. Method: In the present work, docking and 3D-QSAR techniques were performed on a series of diaminopyrimidine derivatives as FLT3 kinase antagonists. Results: Docking study recognized important active site residues such as Leu616, Gly617, Val624, Ala642, Phe830, Tyr693, Cys694, Cys695, Tyr696 and Gly697 that participate in the inhibition of FLT3 kinase. Receptor-based CoMFA, RF-CoMFA and CoMSIA models were developed. RFCoMFA model revealed relatively better statistical results compared to other models. Furthermore, the selected RF-CoMFA model was evaluated using various validation techniques. Contour maps of the RF-CoMFA illustrated that steric and electronegative substitutions were favored at R1 position whereas steric and electropositive substitutions were favored at R2 position to enhance the potency. Conclusion: Based on the designed strategy, we derived from the contour map analysis, 14 novel FLT3 inhibitors were designed and their activities were predicted. These designed inhibitors exhibited more potent activity than the most active compounds of the dataset.

Optimization of a Benzothiazole Indolene Scaffold Targeting Bacterial Cell Wall Assembly.

BackgroundThe bacterial cell envelope is comprised of the cell membrane and the cell wall. The bacterial cell wall provides rigidity to the cell and protects the organism from potential harmful substances also. Cell wall biosynthesis is an important physiological process for bacterial survival and thus has been a primary target for the development of antibacterials. Antimicrobial peptides that target bacterial cell wall assembly are abundant and many bind to the essential cell wall precursor molecule Lipid II.MethodsWe describe the structure-to-activity (SAR) relationship of an antimicrobial peptide-derived small molecule 7771–0701 that acts as a novel agent against cell wall biosynthesis. Derivatives of compound 7771–0701 (2-[(1E)-3-[(2E)-5,6-dimethyl-3-(prop-2-en-1-yl)-1,3-benzothiazol-2-ylidene]prop-1-en-1-yl]-1,3,3-trimethylindol-1-ium) were generated by medicinal chemistry guided by Computer-Aided Drug Design and NMR. Derivatives were tested for antibacterial activity and Lipid II binding.ResultsOur results show that the N-alkyl moiety is subject to change without affecting functionality and further show the functional importance of the sulfur in the scaffold. The greatest potency against Gram-positive bacteria and Lipid II affinity was achieved by incorporation of a bromide at the R3 position of the benzothiazole ring.ConclusionWe identify optimized small molecule benzothiazole indolene scaffolds that bind to Lipid II for further development as antibacterial therapeutics.

Structure-activity Relationship Study on Therapeutically Relevant EGFR Double Mutant Inhibitors.

EGFR is a clinically approved drug target in cancer. The first generation tyrosine kinase inhibitors targeting L858R mutated EGFR are routinely used to treat non-small cell lung cancer (NSCLC). However, the presence of a secondary mutation (T790M) tenders these inhibitors ineffective and thus results in the relapse of the disease. New reversible inhibitors are required, which act against T790M/L858R (TMLR) double mutants and overcome resistance. In the present study, various Fragment based QSAR (G-QSAR) models along with interaction terms have been studied for amino-pyrimidine derivatives having biological activity against TMLR mutant enzyme. The G-QSAR models developed using partial least squares regression via stepwise forward- backward variable selection technique showed the best results. The model showed a high correlation coefficient (r² = 0.86), cross-validation coefficient (q² = 0.81) and predicted correlation (predicted r² = 0.62), which indicated that the model is robust and predictive. Based on the model, it was revealed that at R1 position increasing saturated carbon (number of -CH atom connected with 3 single bonds i.e. SsssCHcount) and retention index (chi3) is desired for the enhancement of bioactivity. Additionally, at the R2 position, increasing lipophilic character (slogp) and at site R3, the polarizability of compound need to be increased for better inhibitory activity. We further studied the contribution of interactions among significant descriptors in enhancing the activity of the compounds. It revealed that the presence of Sum((R1-SsssCHcount, R2-slogp) and Mult(R1-chi3, R3-polarizabilityAHC) are the most significantly influencing descriptors. We further compared the variation in the most and least active compounds which established that retention of the above properties is essential for imparting significant inhibitory activity to these molecules. The study provides site specific information wherein chemical group variation influences the inhibitory potency of TMLR amino-pyrimidine inhibitors, which can be used for designing new molecules with the desired activity.

3D-QSAR Analysis and Molecular Docking Studies on 3-Arylcoumarin Derivatives as Potential α- Glucosidase Inhibitors

α-glucosidase inhibitors (AGI) are the structural moieties that are found to be of utmost importance in the fields of pharmacy and which involves delaying the absorption of carbohydrates by blocking of alpha-glucosidase enzyme in the brush border of small intestine and plays an important role in constituting a promising therapeutic class against diabetic disease (Type II). In this study, the three-dimensional quantitative structure-activity relationship (3D-QSAR) and docking models were developed using Fujito-Ban analysis in VALSTAT software and Molegro Virtual Docker 6.0. The theoretical models were generated from 29 3-arylcoumarin inhibitors of α-glucosidase. A robust QSAR model with good prediction in internal and external verification was constructed, where r2 and q2 were 0.821 and 0.646 respectively. The QSAR study suggested that substitution of group at R1 position on 3-arylcoumarin ring with electron withdrawing group favourable for the anti-diabetic activity. Molecular docking studies were performed with the coordinates of the α-glucosidase crystal structure (PDB ID: 3WY2), as the results we found that the ligands would form the hydrogen bond interactions with Asp 202, Arg 400 and Glu 271 of the protein receptor generally. For better α-glucosidase inhibitory activity, dipole seems to give good results. These results of the QSAR analysis and molecular docking provided some useful information for designing new and effective α-glucosidase inhibitors in significance of stability and the binding interaction between ligand the receptor site by considering the validation parameters.

Benzoxazines as new human topoisomerase I inhibitors and potential poisons.

The numbers of topoisomerase I targeted drugs on the market are very limited although they are used clinically for treatment of solid tumors. Hence, studies about finding new chemical structures which specifically target topoisomerase I are still remarkable. In this present study, we tested previously synthesized 3,4-dihydro-2H-1,4-benzoxazin-3-one derivatives to reveal their human DNA topoisomerase I inhibitory potentials. We investigated inhibitory activities of 3,4-dihydro-2H-1,4-benzoxazin-3-one derivatives on human topoisomerase I by relaxation assay to clarify inhibition mechanisms of effective derivatives with EMSA and T4 DNA ligase based intercalation assay. With SAR study, it was tried to find out effective groups in the ring system. While 10 compounds showed catalytic inhibitory activity, 8 compounds were found to be potential topoisomerase poisons. 4 of them also exhibited both activities. 2-hydroxy-3,4-dihydro-2H-1,4-benzoxazin-3-one (BONC-001) was the most effective catalytic inhibitor (IC50:8.34mM) and ethyl 6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-acetate (BONC-013) was the strongest potential poison (IC50:0.0006mM). BONC-013 was much more poisonous than camptothecin (IC50:0.034mM). Intercalation assay showed that BONC-013 was not an intercalator and BONC-001 most probably prevented enzyme-substrate binding in an unknown way. Another important result of this study was that OH group instead of ethoxycarbonylmethyl group at R position of benzoxazine ring was important for hTopo I catalytic inhibition while the attachment of a methyl group of R1 position at R2 position were play a role for increasing of its poisonous effect. As a result, we presented new DNA topoisomerase I inhibitors which might serve novel constructs for future anticancer agent designs. Graphical abstract.

(R)-2-Phenyl-4,5-Dihydrothiazole-4-Carboxamide Derivatives Containing a Diacylhydrazine Group: Synthesis, Biological Evaluation, and SARs.

A series of (R)-2-phenyl-4,5-dihydrothiazole-4-carboxamide derivatives containing a diacylhydrazine moiety were designed and synthesized. Their structures were confirmed by melting points, 1H NMR, 13C NMR, and elemental analysis (EA). Their antifungal and insecticidal activities were evaluated. The antifungal activity result indicated that most title compounds against Cercospora arachidicola, Alternaria solani, Phytophthora capsici, and Physalospora piricola exhibited apparent antifungal activities at 50 mg/L, and better than chlorothalonil or carbendazim. The EC50 values of (R)-N’-benzoyl-2-(4-chlorophenyl)-4,5-dihydrothiazole-4-carbohydrazide (I-5) against six tested phytopathogenic fungi were comparable to those of chlorothalonil. The CoMSIA model showed that a proper hydrophilic group in the R1 position, as well as a proper hydrophilic and electron-donating group in the R2 position, could improve the antifungal activity against Physalospora piricola, which contributed to the further optimization of the structures. Meanwhile, most title compounds displayed good insecticidal activities, especially compound (R)-N’-(4-nitrobenzoyl)-2-(4-nitrophenyl)-4,5-dihydrothiazole-4-carbohydrazide (III-3). The insecticidal mechanism results indicated that compound III-3 can serve as effective insect Ca2+ level modulators by disrupting the cellular calcium homeostasis in Mythimna separata.

3D-QSAR, molecular docking, and molecular dynamics simulation of a novel thieno[3,4-d]pyrimidine inhibitor targeting human immunodeficiency virus type 1 reverse transcriptase

Human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) is one of the most attractive drug targets for the treatment of AIDS. In this study, 67 thieno[3,4-d]pyrimidine derivatives were selected as novel HIV-1 RT inhibitors to combat viral resistance, and were subjected to 3 D-QSAR studies using CoMFA, CoMSIA, and T-CoMFA. In the 3 D-QSAR study, two methods of ligand-based alignment and pharmacophore-based alignment were used. The results showed that CoMFA (n = 8; q2 = 0.594; r2 = 0.974) and CoMSIA (n = 7; q2 = 0.528; r2 = 0.965) have good stability and predictability. The molecular docking study showed that the hydrogen bonding and van der Waals interactions of key residues such as Leu100, Lys101, Val106, Phe227 and Pro236 play an important role in ligand-receptor binding. Based on these results, 12 new thieno[3,4-d]pyrimidines were designed and their activities were predicted; the results indicated that these compounds have good predictive activity and reasonably good ADME/T profiles. MD simulation analysis of 50 ns showed that compound 23j formed four hydrogen bonds with the residues (Lys101, Lys104, Val106 and Thr318), and binds more closely to HIV-1 RT than compound 23j. Furthermore, the group at the R1 position and the horseshoe-like conformation of these compounds are critical for the inhibitory activity and stability. These results provide useful insights for the discovery and design of a new generation of HIV-1 RT inhibitors.Communicated by Ramaswamy H. Sarma

Amino-3,5-Dicyanopyridines Targeting the Adenosine Receptors Ranging from Pan Ligands to Combined A1/A2B Partial Agonists.

The amino-3,5-dicyanopyridine derivatives belong to an intriguing series of adenosine receptor (AR) ligands that has been developed by both academic researchers and industry. Indeed, the studies carried out to date underline the versatility of the dicyanopyridine scaffold to obtain AR ligands with not only a wide range of affinities but also with diverse degrees of efficacies at the different ARs. These observations prompted us to investigate on the structure–activity relationships (SARs) of this series leading to important previously reported results. The present SAR study has helped to confirm the 1H-imidazol-2-yl group at R2 position as an important feature for producing potent AR agonists. Moreover, the nature of the R1 substituent highly affects not only affinity/activity at the hA1 and hA2B ARs but also selectivity versus the other subtypes. Potent hA1 and hA2B AR ligands were developed, and among them, the 2-amino-6-[(1H-imidazol-2-ylmethyl)sulfanyl]-4-[4-(prop-2-en-1-yloxy)phenyl]pyridine-3,5-dicarbonitrile (3) is active in the low nanomolar range at these subtypes and shows a good trend of selectivity versus both the hA2A and hA3 ARs. This combined hA1/hA2B partial agonist activity leads to a synergistic effect on glucose homeostasis and could potentially be beneficial in treating diabetes and related complications.

On the performance of molecular tailoring approach for estimation of the intramolecular hydrogen bond energies of RAHB systems: a comparative study

In the current research, the performance of molecular tailoring approach (MTA) for estimation of the intramolecular hydrogen bond (IMHB) energies of the simple resonance-assisted hydrogen bond (RAHB) systems was theoretically investigated. First, a wide range of malonaldehyde derivatives (36 members) including the F, Cl, Br, CN, NO2, ethen (-CH=CH2), ethin (-C ≡ CH), CF3, OCH3, C2H5, CH3, and Ph substitutions at R1, R2, and R3 positions were considered. Then, all of these molecules at MP2/6-311++G(d, p) level of theory have been optimized and their MTA energies were calculated. Furthermore, various qualitative descriptors of IMHB such as structural, spectroscopic, topological, and molecular orbital parameters were considered, and all of correlations between these factors and MTA energies were explored. According to their regression coefficients (R2), the linear characteristic of correlations obeys the following order:$$ {H}_{\mathrm{H}\dots \mathrm{O}}>{d}_{\mathrm{O}-\mathrm{H}}>{E}_{\mathrm{CT}}>{V}_{\mathrm{H}\bullet \bullet \bullet \mathrm{O}}>{\rho}_{\mathrm{H}\bullet \bullet \bullet \mathrm{O}}>{\nu}_{\mathrm{O}-\mathrm{H}}>{d}_{\mathrm{H}\bullet \bullet \bullet \mathrm{O}}>{d}_{\mathrm{O}\bullet \bullet \bullet \mathrm{O}} $$$$ 0.952\kern1.5em 0.940\kern1.2em 0.936\kern0.75em 0.914\kern1.2em 0.901\kern1.2em 0.834\kern1em 0.789\kern1.3em 0.755 $$ These correlation coefficients have compared with the corresponding R2 values of other models such as RRM, RBM, GCM, IRM, and OCM, which leads to the following order of linearity:$$ \mathrm{MTA}\ge \mathrm{RRM}>\mathrm{RBM}>\mathrm{GCM}>\mathrm{IRM}>\mathrm{OCM}. $$ Finally, the significance of π-electron delocalization (π-ED) of RAHB rings is also evaluated by the geometrical factor of Gilli (λ) and the harmonic oscillator model of aromaticity (HOMA) that presents the excellent linear correlations with MTA energies, which may be implied on the validity of RAHB theory.

A comparative study of intramolecular hydrogen bond on N-formylformamide derivatives in ground and first singlet excited state: a DFT and TD-DFT study

Intramolecular hydrogen bond (IHB) of N-formylformamide derivatives in the both ground (GS) and first singlet excited state (S1) have been investigated by DFT and TD-DFT methods with the standard basis set 6-311++G (d,p), respectively. Also the potential energy density method was used to calculate of the IHB energies in the both GS and S1. Our calculations show that IHB energies in the GS are much higher than the S1 one. In order to explain this energy difference, molecular orbital analysis (MOS) has been employed. According to the MOS, it was found that electron density on antibonding orbital (δ O–H * ) increases after excitation, which can be a reason for the weakened IHB in the S1. In this work, we evaluated and compared the substitution effects on the IHB strength in the both GS and S1 by some of the IHB descriptors such as geometrical, topological and orbital charge transfer parameters. The results proved that the substitution effects on the both GS and S1 are same. As with replacing of the halogen atoms at R2 position the IHB energies increased while for the R2 and R1,2 decreased. Moreover, for the first time, various geometry—based resonance indices such as Gilli (Q and λ) parameters, original harmonic oscillator model of aromaticity, harmonic oscillator model of electron delocalization and harmonic oscillator model for heterocyclic with π-electrons delocalization were calculated and compared in the both GS and S1. Interestingly, it is found from the resonance indices that electron delocalization in the S1 increased that this result is against the RAHB theory in the studied molecules. Finally, the linear equations of the IHB energies versus the IHB descriptors parameters and resonance indices in the both GS and S1 indicate that the potential energy density is an inappropriate method for calculation of the IHB energies of the heterocyclic RAHB systems in the S1.

A theoretical study of the absorption spectra of electron-deficient pentacene derivatives using DFT and TDDFT.

Non-fullerene acceptor based organic bulk heterojunction solar cells have been a hot topic because their power conversion efficiencies have been up to 16.35%. Functionalized 6,13‑bis (trimethylsilyl alkynyl) pentacenes with strong electron withdrawing groups, which can be easily modified to improve charge transport properties and film morphology, seem to be promising soluble non-fullerene pentacene-based organic acceptors. But how the substitutions of electron withdrawing groups influence their electronic structures, then change the absorption spectra and power conversion efficiencies, is still not clear. In this paper, we utilize density functional theory and time-dependent density functional theory to study the effects of substitutions of different electron withdrawing groups (CN, CF3, NO2) and different positions of these groups in 6,13‑bis (trimethylsilyl alkyl) pentacene molecule on their physical and optical properties. We find that the experimental power conversion efficiencies are positively/negatively correlated with calculated dipole moments/exciton binding energies of these functionalized molecules. The computed results indicate that the molecules substituted with CN group have much larger dipole moment than the others. For the same electron withdrawing group, the dipole moment at the R2 position is generally larger than that at the R1 position. Furthermore, we find that the calculated exciton binding energy of these molecules functionalized at the R2 position is lower than that at the R1 position. In addition, the result of absorption spectra confirm that these functionalized 6,13‑bis (trimethylsilyl alkynyl) pentacenes have stronger absorption strength than C60 in the both visible and the ultraviolet regions.

Designing of novel ERRγ inverse agonists by molecular modeling studies of docking and 3D-QSAR on hydroxytamoxifen derivatives

ERRγinverse agonist is a powerful therapeutic target for the treatment of cancers and certain metabolic disorders. Until now, only GSK5814 was reported as selective ERRγinverse agonist. So 60 newly hydroxytamoxifen analogues were selected to perform molecular docking and 3D-QSAR study to design more selective inverse agonist of ERRγ. Both established CoMFA and CoMSIA models obtained high predictive and satisfactory value, demonstrated that bulky, hydrophobic and negative electrostatic substitutions are preferred at R2 position, and introducing hydrophilic and H-bond donor and acceptor groups at R1 and R4 positions is greatly important for improving binding activities. The obtained information will be useful to provide clues for rationally designing novel and high potency ERRγinverse agonists.

A Combined Molecular Docking and 3D‐QSAR Studies on Tetrahydropteridin Derivatives as PLK2 Antagonists

Polo‐like kinase‐2 (PLK2) is a member of a highly conserved serine/threonine kinase family. PLK2 is implicated in the regulation of cell division. It is activated in the early G1 phase in cell cycle progression and is required for centriole duplication. It has been observed that the low expression of PLK2 leads to B‐cell lymphoma and ovarian cancer. Furthermore, it was found to be associated with poor prognosis in non‐small cell lung cancer, breast cancer, head and neck carcinoma, and osteosarcoma. Thus, PLK2 is considered as an important therapeutic target for cancer drug design due to its multiple roles in several types of cancers. In this work, molecular docking and 3D‐QSAR techniques were performed on tetrahydropteridin derivatives as PLK2 inhibitors. Docking study identified crucial active site residues such as Leu88, Cys96, Ala109, Lys111, Val143, Leu159, Glu160, Cys162, and Phe212 which helps in the firm binding of the ligand. Receptor‐guided CoMFA (q 2 = 0.859, NOC = 5, r 2 = 0.996) and CoMSIA (q 2 = 0.855, NOC = 6, r 2 = 0.998) models were produced. The predictability and stability of these models were assessed using different validation techniques. Contour maps revealed that electrostatic and steric substitutions were favorable at R1 and R2 positions respectively. In addition, the substitution of H‐bond donor group at the R1 position was also favored. The results of this study could be helpful for designing more potent PLK2 inhibitors.

Preparation and biological evaluation of soluble tetrapeptide epoxyketone proteasome inhibitors

A series of novel tetrapeptidyl epoxyketone inhibitors of 20S proteasome was designed and synthesized. To fully understand the SAR, various groups at R1, R2, R3, R4 and R5 positions, including aromatic and aliphatic substituents were designed, synthesized and biologically assayed. Based on the enzymatic results, seven compounds were selected to evaluate their cellular activities and soluble compound 36 showed strong potency against human multiple myeloma (MM) cell lines. Microsomal stability results indicated that compound 36 was more stable in mice, rat and human microsomes than marketed carfilzomib. The in vivo activities of this compound were evaluated with the xenograft mice models of MM cell lines ARH77 and RPMI-8226 with luciferase expression and the T/C value of the two models were 49.5% and 37.6%, respectively. To evaluate the potential cardiovascular toxicity, inhibition of hERG ion channel in HEK293 cells by compound 36 and carfilzomib was carried out. The results indicated that 36 had no binding affinity for the hERG ion channel while carfilzomib could bind it with IC50 of 92.1 μM.

Co-adsorbing effect of bile acids containing bulky amide groups at 3β-position on the photovoltaic performance in dye-sensitized solar cells

Co-adsorbing molecules attain certain control in the surrounding of the dyes leading to enhanced efficiencies mainly by affecting the recombination of the photogenerated electrons and aggregation of dyes. Bile acids such as deoxycholic acid (DOA) and chenodeoxycholic acid (CDOA) yield competitive photovoltaic parameters. We harness the steroid backbone of bile acids to chemically modified it at its R3 position attaching sterically demanding amide groups rather than typically terminal hydroxyl groups (3β-position) as in DOA and CDOA. All possible resultant effects on the performance in complete DSSCs were studied by current density-voltage curves (e.g., percentage of efficiency, %η; open-circuit voltage, Voc; short-circuit photocurrent, Jsc; and fill factor, FF), incident photon-to-current conversion efficiency (IPCE), and a set of interfacial data by electrochemical impedance spectroscopy (EIS). Our co-adsorbates stand out by enhancing the conversion efficiencies, being in some cases competitive with photovoltaic parameters of DOA and CDOA.

Design, synthesis, and biological evaluation of polyphenols with 4,6-diphenylpyrimidin-2-amine derivatives for inhibition of Aurora kinase A

Several 4,6-diarylpyrimidin-2-amine derivatives show anticancer properties. However, their mode of action is not fully characterized. To develop potent anticancer chemotherapeutic agents, we designed and synthesized 25 4,6-diphenylpyrimidin-2-amine derivatives containing a guanidine moiety. Clonogenic long-term survival assays were performed to screen anticancer compounds. To derive the structural conditions showing good cytotoxicities against cancer cells, quantitative structure-activity relationships (QSAR) were calculated. Biological activities were determined by flow cytometry for cell cycle analysis and by immunoblot analysis for the detection of Aurora kinase A (AURKA) activity. Because 2-(2-Amino-6-(2,4-dimethoxyphenyl)pyrimidin-4-yl) phenol (derivative 12) selectively inhibited AURKA activity from the kinome assay, in silico docking experiments were performed to elucidate the molecular binding mode between derivative 12 and AURKA. The pharmacophores were derived based on the QSAR calculations. Derivative 12 inhibited AURKA activity and reduced phosphorylation of AURKA at Thr283 in HCT116 human colon cancer cells. Derivative 12 caused the accumulation of the G2/M phase of the cell cycle and triggered the cleavages of caspase-3, caspase -7, and poly(ADP-ribose) polymerase. The binding energies of 30 apo-AURKA - derivative 12 complexes obtained from in silico docking ranged from -16.72 to -11.63kcal/mol. Derivative 12 is an AURKA inhibitor, which reduces clonogenicity, arrests the cell cycle at the G2/M phase, and induces caspase-mediated apoptotic cell death in HCT116 human colon cancer cells. In silico docking demonstrated that derivative 12 binds to AURKA well. The structure-activity relationship calculations showed hydrophobic substituents and 1-naphthalenyl group at the R2 position increased the activity. The existence of an H-bond acceptor at C-2 of the R1 position increased the activity, too. Graphical abstract Derivative 12 inhibits Aurora kinase A activity and causes the G2/M phase arrest of the cell cycle.

Exploring structural features of EGFR–HER2 dual inhibitors as anti-cancer agents using G-QSAR approach

Simultaneous inhibition of EGFR and HER2 by dual-targeting inhibitors is an established anti-cancer strategy. Therefore, a recent trend in drug discovery involves understanding the features of such dual inhibitors. In this study, three different G-QSAR models were developed corresponding to individual EGFR, HER2 and the dual-model for both receptors. The dual-model provided site-specific information wherein (i) increasing electronegative character and higher index of saturated carbon at R4 position; (ii) presence of chlorine atom at R2 position; (iii) decreasing alpha modified shape index at R1 and R3 positions; and (iv) less electronegativity at R2 position; were found important for enhancing the dual activity. Also, comparison of dual-model with the EGFR/HER2 individual models revealed that it incorporates the properties of both models and, thus, represents a combination of EGFR/HER2. Further, fragment analysis revealed that R2 and R4 are important for imparting high potency while specificity is decided by R1/R3 fragment. We also checked the predictive ability of the dual-model by determining applicability domain using William’s plot. Also, analysis of active molecules showed they show favorable substitutions that agree with the constructed dual-model. Thus, we have been successful in developing a single dual-response QSAR model to get an insight into various structural features influencing EGFR/HER2 activity.

Enhanced photoelectrical properties of alizarin-based natural dye via structure modulation

A series of new dyes (AL01–AL02t) were designed through introducing different conjugated bridges into the position of two hydroxyl groups on the natural dye 1,2-dihydroxyanthraquinone (alizarin), and their photoelectrical properties were systematically investigated as the dyes applied in the field of dye-sensitized solar cell (DSSC) via the density functional theory (DFT) and time-dependent DFT methods. Moreover, the key parameters related to the intramolecular charge transfer (ICT) properties of the dyes, such as the transferred charge and charge transferred distance were calculated. In addition, the light harvesting efficiency, free-energy change driving force, electron regeneration driving force and chemical reactivity parameters were obtained to evaluate the photoelectrical properties of the investigated dyes. The calculated results indicate that the designed dyes would show the better photoelectrical properties, owing to their lower energy gaps, red-shifted absorption spectra, the greater transferred charge and charge transferred distance. Therein, it is worth noting that the designed dye AL02t displays the lowest energy gap, widest absorption spectrum, smallest hole and electron reorganization energies, lowest electron regeneration driving force and chemical hardness, largest electroaccepting power and electrophilicity values, which mean that this designed dye would present the best photoelectrical properties among the investigated dyes. Significantly, the better optical and electrical characteristics of AL02-series dyes than that of AL01-series dyes indicate the modification for the hydroxyl group on R2 position of alizarin is more beneficial to improving its photoelectrical properties, which can provide a valuable reference for synthesizing the dyes with higher efficiency based on natural dyes in experiments.

Receptor‐guided 3D‐QSAR Study of Anilinoquinazolines as RET Receptor Tyrosine Kinase Antagonists

A RET (Rearranged during transfection) kinase belongs to a receptor tyrosine kinase family. It plays a major role in development, maturation, survival, and maintenance of cells and tissues. Oncogenic activation of RET has been reported in numerous cancers. Thus, it is a significant therapeutic target for cancer. Present work covers docking and 3D‐QSAR techniques executed on anilinoquinazoline derivatives as RET kinase antagonists. Docking study recognized important active site amino acid residues like Leu730, Gly731, Gly733, Glu734, Ala807, Gly810, Ser811, and Asp874 which inhibits the RET kinase. In 3D‐QSAR technique, receptor‐guided CoMFA (q2 = 0.723, NOC = 5, r2 = 0.980) as well as CoMSIA (q2 = 0.767, NOC = 6, r2 = 0.967) models were produced. The stabilities of these models were evaluated using diverse validation techniques. Contour maps showed that steric and hydrogen bond donor substitutions are favored at R1 and R2 positions whereas positive and negative substitutions are favored at the R1 position to enhance the potency. In addition, the substitution of H‐bond accepting group to the region which is close to both phenyl and piperazine is favored. Hence, the outcome of this study could be beneficial to design more potent inhibitors for RET kinase.