Three-Dimensional-QSAR and Relative Binding Affinity Estimation of Focal Adhesion Kinase Inhibitors.

Precise binding affinity predictions are essential for structure-based drug discovery (SBDD). Focal adhesion kinase (FAK) is a member of the tyrosine kinase protein family and is overexpressed in a variety of human malignancies. Inhibition of FAK using small molecules is a promising therapeutic option for several types of cancer. Here, we conducted computational modeling of FAK-targeting inhibitors using three-dimensional structure-activity relationship (3D-QSAR), molecular dynamics (MD), and hybrid topology-based free energy perturbation (FEP) methods. The structure-activity relationship (SAR) studies between the physicochemical descriptors and inhibitory activities of the chemical compounds were performed with reasonable statistical accuracy using CoMFA and CoMSIA. These are two well-known 3D-QSAR methods based on the principle of supervised machine learning (ML). Essential information regarding residue-specific binding interactions was determined using MD and MM-PB/GBSA methods. Finally, physics-based relative binding free energy (ΔΔGRBFEA→B) terms of analogous ligands were estimated using alchemical FEP simulation. An acceptable agreement was observed between the experimental and computed relative binding free energies. Overall, the results suggested that using ML and physics-based hybrid approaches could be useful in synergy for the rational optimization of accessible lead compounds with similar scaffolds targeting the FAK receptor.

Binding Studies and Lead Generation of Pteridin-7(8H)-one Derivatives Targeting FLT3.

Ligand modification by substituting chemical groups within the binding pocket is a popular strategy for kinase drug development. In this study, a series of pteridin-7(8H)-one derivatives targeting wild-type FMS-like tyrosine kinase-3 (FLT3) and its D835Y mutant (FL3D835Y) were studied using a combination of molecular modeling techniques, such as docking, molecular dynamics (MD), binding energy calculation, and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies. We determined the protein-ligand binding affinity by employing molecular mechanics Poisson-Boltzmann/generalized Born surface area (MM-PB/GBSA), fast pulling ligand (FPL) simulation, linear interaction energy (LIE), umbrella sampling (US), and free energy perturbation (FEP) scoring functions. The structure-activity relationship (SAR) study was conducted using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), and the results were emphasized as a SAR scheme. In both the CoMFA and CoMSIA models, satisfactory correlation statistics were obtained between the observed and predicted inhibitory activity. The MD and SAR models were co-utilized to design several new compounds, and their inhibitory activities were anticipated using the CoMSIA model. The designed compounds with higher predicted pIC50 values than the most active compound were carried out for binding free energy evaluation to wild-type and mutant receptors using MM-PB/GBSA, LIE, and FEP methods.

Molecular Modeling Studies of N-phenylpyrimidine-4-amine Derivatives for Inhibiting FMS-like Tyrosine Kinase-3.

Overexpression and frequent mutations in FMS-like tyrosine kinase-3 (FLT3) are considered risk factors for severe acute myeloid leukemia (AML). Hyperactive FLT3 induces premature activation of multiple intracellular signaling pathways, resulting in cell proliferation and anti-apoptosis. We conducted the computational modeling studies of 40 pyrimidine-4,6-diamine-based compounds by integrating docking, molecular dynamics, and three-dimensional structure-activity relationship (3D-QSAR). Molecular docking showed that K644, C694, F691, E692, N701, D829, and F830 are critical residues for the binding of ligands at the hydrophobic active site. Molecular dynamics (MD), together with Molecular Mechanics Poison-Boltzmann/Generalized Born Surface Area, i.e., MM-PB(GB)SA, and linear interaction energy (LIE) estimation, provided critical information on the stability and binding affinity of the selected docked compounds. The MD study suggested that the mutation in the gatekeeper residue F691 exhibited a lower binding affinity to the ligand. Although, the mutation in D835 in the activation loop did not exhibit any significant change in the binding energy to the most active compound. We developed the ligand-based comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) models. CoMFA (q2 = 0.802, r2 = 0.983, and QF32 = 0.698) and CoMSIA (q2 = 0.725, r2 = 0.965 and QF32 = 0.668) established the structure-activity relationship (SAR) and showed a reasonable external predictive power. The contour maps from the CoMFA and CoMSIA models could explain valuable information about the favorable and unfavorable positions for chemical group substitution, which can increase or decrease the inhibitory activity of the compounds. In addition, we designed 30 novel compounds, and their predicted pIC50 values were assessed with the CoMSIA model, followed by the assessment of their physicochemical properties, bioavailability, and free energy calculation. The overall outcome could provide valuable information for designing and synthesizing more potent FLT3 inhibitors.

Molecular Modelling Studies on Pyrazole Derivatives for the Design of Potent Rearranged during Transfection Kinase Inhibitors.

RET (rearranged during transfection) kinase, one of the receptor tyrosine kinases, plays a crucial role in the development of the human nervous system. It is also involved in various cell signaling networks responsible for the normal cell division, growth, migration, and survival. Previously reported clinical studies revealed that deregulation or aberrant activation of RET signaling can cause several types of human cancer. For example, medullary thyroid carcinoma (MTC) and multiple endocrine neoplasia (MEN2A, MEN2B) occur due to sporadic mutation or germline RET mutation. A number of RET kinase inhibitors have been approved by the FDA for the treatment of cancer, such as cabozantinib, vandetanib, lenvatinib, and sorafenib. However, each of these drugs is a multikinase inhibitor. Hence, RET is an important therapeutic target for cancer drug design. In this work, we have performed various molecular modelling studies, such as molecular docking and dynamics simulation for the most active compound of the pyrazole series as RET kinase inhibitors. Furthermore, molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) free energy calculation and 3-dimensional quantitative structure-activity relationship (3D-QSAR) were performed using g_mmpbsa and SYBYL-X 2.1 package. The results of this study revealed the crucial binding site residues at the active site of RET kinase and contour map analysis showed important structural characteristics for the design of new highly active inhibitors. Therefore, we have designed ten RET kinase inhibitors, which showed higher inhibitory activity than the most active compound of the series. The results of our study provide insights to design more potent and selective RET kinase inhibitors.

Molecular Modeling Study of c-KIT/PDGFRα Dual Inhibitors for the Treatment of Gastrointestinal Stromal Tumors.

Gastrointestinal stromal tumors (GISTs) are the most common Mesenchymal Neoplasm of the gastrointestinal tract. The tumorigenesis of GISTs has been associated with the gain-of-function mutation and abnormal activation of the stem cell factor receptor (c-KIT) and platelet-derived growth factor receptor alpha (PDGFRα) kinases. Hence, inhibitors that target c-KIT and PDGFRα could be a therapeutic option for the treatment of GISTs. The available approved c-KIT/PDGFRα inhibitors possessed low efficacy with off-target effects, which necessitated the development of potent inhibitors. We performed computational studies of 48 pyrazolopyridine derivatives that showed inhibitory activity against c-KIT and PDGFRα to study the structural properties important for inhibition of both the kinases. The derivative of phenylurea, which has high activities for both c-KIT (pIC50 = 8.6) and PDGFRα (pIC50 = 8.1), was used as the representative compound for the dataset. Molecular docking and molecular dynamics simulation (100 ns) of compound 14 was performed. Compound 14 showed the formation of hydrogen bonding with Cys673, Glu640, and Asp810 in c-KIT, and Cys677, Glu644, and Asp836 in PDGFRα. The results also suggested that Thr670/T674 substitution in c-KIT/PDGFRα induced conformational changes at the binding site of the receptors. Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were developed based on the inhibitors. Contour map analysis showed that electropositive and bulky substituents at the para-position and the meta-position of the benzyl ring of compound 14 was favorable and may increase the inhibitory activity against both c-KIT and PDGFRα. Analysis of the results suggested that having bulky and hydrophobic substituents that extend into the hydrophobic pocket of the binding site increases the activity for both c-KIT and PDGFRα. Based on the contour map analysis, 50 compounds were designed, and the activities were predicted. An evaluation of binding free energy showed that eight of the designed compounds have potential binding affinity with c-KIT/PDGFRα. Absorption, distribution, metabolism, excretion and toxicity (ADMET) and synthetic feasibility tests showed that the designed compounds have reasonable pharmaceutical properties and synthetic feasibility. Further experimental study of the designed compounds is recommended. The structural information from this study could provide useful insight into the future development of c-KIT and PDGFRα inhibitors.

High-temperature in situ crystallographic observation of reversible gas sorption in impermeable organic cages.

Crystallographic observation of adsorbed gas molecules is a highly difficult task due to their rapid motion. Here, we report the in situ single-crystal and synchrotron powder X-ray observations of reversible CO2 sorption processes in an apparently nonporous organic crystal under varying pressures at high temperatures. The host material is formed by hydrogen bond network between 1,3,5-tris-(4-carboxyphenyl)benzene (H3BTB) and N,N-dimethylformamide (DMF) and by π-π stacking between the H3BTB moieties. The material can be viewed as a well-ordered array of cages, which are tight packed with each other so that the cages are inaccessible from outside. Thus, the host is practically nonporous. Despite the absence of permanent pathways connecting the empty cages, they are permeable to CO2 at high temperatures due to thermally activated molecular gating, and the weakly confined CO2 molecules in the cages allow direct detection by in situ single-crystal X-ray diffraction at 323 K. Variable-temperature in situ synchrotron powder X-ray diffraction studies also show that the CO2 sorption is reversible and driven by temperature increase. Solid-state magic angle spinning NMR defines the interactions of CO2 with the organic framework and dynamic motion of CO2 in cages. The reversible sorption is attributed to the dynamic motion of the DMF molecules combined with the axial motions/angular fluctuations of CO2 (a series of transient opening/closing of compartments enabling CO2 molecule passage), as revealed from NMR and simulations. This temperature-driven transient molecular gating can store gaseous molecules in ordered arrays toward unique collective properties and release them for ready use.

In silico study of 1-(4-Phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl) ethanones derivatives as CCR1 antagonist: homology modeling, docking and 3D-QSAR approach.

C-C chemokine receptor type 1 (CCR1) is a chemokine receptor with seven transmembrane helices and it belongs to the G-Protein Coupled receptor (GPCR) family. It plays an important role in rheumatoid arthritis, organ transplant rejection, Alzheimer's disease and also causes inflammation. Because of its role in disease processes, CCR1 is considered to be an important drug target. In the present study, we have performed three dimensional Quantitative Structure activity relationship (3D-QSAR) studies on a series of 1-(4-Phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl) ethanone derivatives targeting CCR1. Homology modeling of CCR1 was performed based on a template structure (4EA3) which has a high sequence identity and resolution. The highest active molecule was docked into this model. Ligand-based and Receptor-based quantitative structure-activity relationship (QSAR) study was performed and CoMFA models with reasonable statistics was developed for both ligand-based (q(2)=0.606; r(2)=0.968) and receptor-guided (q(2)=0.640; r(2)=0.932) alignment methods. Contour map analyses identified favorable regions for high affinity binding. The docking results highlighted the important active site residues. Tyr113 was found to interact with the ligand through hydrogen bonding. This residue has been considered responsible for anchoring ligands inside the active site. Our results could also be helpful to understand the inhibitory mechanism of 1-(4-Phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl) ethanone derivatives thereby to design more effective ligands in the future.

Dihydrogen phosphate as a hydrogen-bonding donor element: anion receptors based on acylhydrazone.

Chromogenic anion receptors based on acylhydrazone are designed and synthesized. UV-vis and (1)H NMR titration showed that receptors 1 and 2 are selective receptors for dihydrogen phosphate (H2PO4(-)). Both showed strong association constants with H2PO4(-) even in polar solvents. Receptor 1 was found to recognize H2PO4(-) through three types of hydrogen-bonding (H-bonding) donors: indole N-H, amide N-H, and imine C-H hydrogens. However, receptor 2 seemed to sense H2PO4(-) through two types of H-bonding donors. Despite this seemingly different number of H-bonding elements, the binding constants of receptors 1 and 2 with H2PO4(-) were almost equal. To understand this puzzling result, we investigated the binding poses of complexes using density functional theory. The proposed 2·H2PO4(-) complex structure revealed another possible H-bonding element involving an aromatic nitrogen acting as a H-bonding acceptor. To confirm this, we synthesized receptor 3, which is devoid of this nitrogen. The binding constant of receptor 3 for H2PO4(-) was 2 orders of magnitude lower than those of receptors 1 and 2. This decreased binding affinity strongly supports the existence of a N(aromatic)···H-O(phosphate) interaction. These results provide a rare opportunity to identify H2PO4(-) acting as a H-bonding donor during an anion-recognition event.

In silico binding free energy predictability with π-π interaction energy-augmented scoring function: benzimidazole Raf inhibitors as a case study.

The ability to estimate binding affinities of ligands precisely is of paramount importance in designing drugs. Docking programs are used primarily to predict the binding mode of ligands to receptors. However, current scoring functions as used in docking programs are not reliable enough to predict binding affinities of ligands without any further calculations. In the present study, we investigate the usefulness of adding π-π interaction energies between ring groups of residues and ligands to the scoring function for docking. It is found that such addition helps ranking ligand activities more correctly. LMP2 calculation is used to measure π-π interaction energies between ring groups. The result of this simple addition shows possibility of π-π interaction generalization in scoring functions.

Structural Insights from Molecular Modeling of Isoindolin-1-One Derivatives as PI3Kγ Inhibitors against Gastric Carcinoma.

The upregulation of phosphoinositol-3-kinase γ (PI3Kγ) is deemed to be positively correlated with tumor-associated-macrophage (TAM)-mediated gastric carcinoma (GC). PI3Kγ suppresses tumor necrosis factor-alpha (TNF-α) and interleukin-12 (IL-12) through activation of the AKT/mTOR pathway, which promotes the immunosuppressant phenotype of TAM. Unlike α and ß isoforms, δ and γ isoforms are primarily distributed in leucocytes and macrophages. Dual inhibitors against PI3Kδ and PI3Kγ have been proven to have merits in targeting solid tumors. Furthermore, it has been found that PI3Kδ is activated by cytokines, while PI3Kγ is activated by G-protein-coupled receptors (GPCRs). This facilitates determining the functional difference between these two isoforms. For this goal, selective inhibitors would be immensely helpful. In the current manuscript, we conducted various molecular modeling studies with a series of isoindolin-1-one derivatives as potent PI3Kγ inhibitors by combining molecular docking, molecular dynamics (MD), molecular mechanics, Poisson-Boltzmann/generalized Born surface area (MM-PB/GBSA) binding free energy calculation, and three-dimensional structure-activity relationship (3D-QSAR) study. To evaluate the selectivity of γ isoform over δ, the molecular modeling studies of idelalisib analogs reported as PI3Kδ inhibitors were also investigated. The contour polyhedrons were generated from the comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) around the ligand-bound active site for both isoforms, which could emphasize plausible explanations for the physicochemical factors that affect selective ligand recognition. The binding modalities of the two isoforms using CoMFA and MD models were compared, which suggested some key differences in the molecular interactions with the ligands and could be summarized as three subsites (one affinity subsite near the C-helix and DFG and two hydrophobic subsites). In the context of the structure-activity relationship (SAR), several new compounds were designed using a fragment-substitution strategy with the aim of selectively targeting PI3Kγ. The pIC50 values of the designed compounds were predicted by the 3D-QSAR models, followed by the MM-PB/GBSA binding energy estimation. The overall findings suggest that the designed compounds have the potential to be used as PI3Kγ inhibitors with a higher binding affinity and selectivity.

In silico quantitative structure-activity relationship studies on P-gp modulators of tetrahydroisoquinoline-ethyl-phenylamine series.

BACKGROUND: Multidrug resistance (MDR) is a major obstacle in cancer chemotherapy. The drug efflux by a transport protein is the main reason for MDR. In humans, MDR mainly occurs when the ATP-binding cassette (ABC) family of proteins is overexpressed simultaneously. P-glycoprotein (P-gp) is most commonly associated with human MDR; it utilizes energy from adenosine triphosphate (ATP) to transport a number of substrates out of cells against concentration gradients. By the active transport of substrates against concentration gradients, intracellular concentrations of substrates are decreased. This leads to the cause of failure in cancer chemotherapy. RESULTS: Herein, we report Topomer CoMFA (Comparative Molecular Field Analysis) and HQSAR (Hologram Quantitative Structure Activity Relationship) models for third generation MDR modulators. The Topomer CoMFA model showed good correlation between the actual and predicted values for training set molecules. The developed model showed cross validated correlation coefficient (q2) = 0.536 and non-cross validated correlation coefficient (r2) = 0.975 with eight components. The best HQSAR model (q2 = 0.777, r2 = 0.956) with 5-8 atom counts was used to predict the activity of test set compounds. Both models were validated using test set compounds, and gave a good predictive values of 0.604 and 0.730. CONCLUSIONS: The contour map near R1 indicates that substitution of a bulkier and polar group to the ortho position of the benzene ring enhances the inhibitory effect. This explains why compounds with a nitro group have good inhibitory potency. Molecular fragment analyses shed light on some essential structural and topological features of third generation MDR modulators. Fragments analysis showed that the presence of tertiary nitrogen, a central phenyl ring and an aromatic dimethoxy group contributed to the inhibitory effect. Based on contour map information and fragment information, five new molecules with variable R1 substituents were designed. The activity of these designed molecules was predicted by the Topomer CoMFA and HQSAR models. The novel compounds showed higher potency than existing compounds.

Molecular modeling studies of pyrrolo[2,3-d]pyrimidin-4-amine derivatives as JAK1 inhibitors based on 3D-QSAR, molecular docking, molecular dynamics (MD) and MM-PBSA calculations.

Rheumatoid Arthritis (RA) is an autoimmune disease caused by overproduction of pro-inflammatory cytokines. Janus Kinases (JAKs) mediate cytokines signaling through the Janus Kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways. Clinical studies have shown that Janus kinase 1 (JAK1) mediated signaling plays a key role in synovial response in rheumatoid arthritis. Hence, the inhibition JAK1 is considered as an important therapeutic route for treatment of rheumatoid arthritis. In this study, we have performed three-dimensional quantitative structure-activity relationship (3 D-QSAR), molecular docking, molecular dynamics (MD) and free energy calculations on a series of pyrrolo[2,3-d]pyrimidin-4-amine JAK1 inhibitors. Molecular docking studies of the compounds 03, 13, 36 and 49 with JAK1 were performed to study the binding interactions. The binding conformations of the compounds from docking studies were selected based on binding energy and H-bond interactions and were used as initial structure for MD simulations. Using 3 D-QSAR techniques, a ligand-based comparative molecular field analysis (CoMFA) model (q2 = 0.5, r2 = 0.96) and a receptor-based CoMFA model (q2 = 0.78, r2 = 0.98) were developed. Analysis of the MD results of the most active compound (compound 49) with JAK1 showed the formation of H-bond interactions with residues Glu957, Leu959 and Gly887 and water-mediated H-bond interaction with Gly887 and His885. Based on the contour map analyses of the receptor-based CoMFA, a design strategy was proposed and was used for designing new JAK1 inhibitors. Four of the designed compounds (D57, D58, D98 and D99) showed predicted activity values (pIC50> 8.8) greater than the most active compound for JAK1. MM-PBSA based free energy calculations indicated that the designed compounds were able to form stable binding with JAK1 primarily through electrostatic interactions and van der Waal interactions. Collectively, the outcome of this study can be used to further the progress of JAK1 inhibition for the treatment of rheumatoid arthritis. Communicated by Ramaswamy H. Sarma.

Computer aided designing of novel pyrrolopyridine derivatives as JAK1 inhibitors.

Janus kinases (JAKs) are a family of non-receptor kinases that play a key role in cytokine signaling and their aberrant activities are associated with the pathogenesis of various immune diseases. The JAK1 isoform plays an essential role in the types 1 and II interferon signaling and elicits signals from the interleukin-2, interleukin-4, gp130, and class 2 receptor families. It is ubiquitously expressed in humans and its overexpression has been linked with autoimmune diseases such as myeloproliferative neoplasm. Although JAK1 inhibitors such as Tofacitinib have been approved for medical use, the low potency and off-target effects of these inhibitors have limited their use and calls for the development of novel JAK1 inhibitors. In this study, we used computational methods on a series of pyrrolopyridine derivatives to design new JAK1 inhibitors. Molecular docking and molecular dynamics simulation methods were used to study the protein-inhibitor interactions. 3D-quantitative structure-activity relationship models were developed and were used to predict the activity of newly designed compounds. Free energy calculation methods were used to study the binding affinity of the inhibitors with JAK1. Of the designed compounds, seventeen of the compounds showed a higher binding energy value than the most active compound in the dataset and at least six of the compounds showed higher binding energy value than the pan JAK inhibitor Tofacitinib. The findings made in this study could be utilized for the further development of JAK1 inhibitors.

Designing of the N-ethyl-4-(pyridin-4-yl)benzamide based potent ROCK1 inhibitors using docking, molecular dynamics, and 3D-QSAR.

Rho-associated kinase-1 (ROCK1) has been recognized for its pivotal role in heart diseases, different types of malignancy, and many neurological disorders. Hyperactivity of ROCK phosphorylates the protein kinase-C (PKC), which ultimately induces smooth muscle cell contraction in the vascular system. Inhibition of ROCK1 has been shown to be a promising therapy for patients with cardiovascular disease. In this study, we have conducted molecular modeling techniques such as docking, molecular dynamics (MD), and 3-Dimensional structure-activity relationship (3D-QSAR) on a series of N-ethyl-4-(pyridin-4-yl)benzamide-based compounds. Docking and MD showed critical interactions and binding affinities between ROCK1 and its inhibitors. To establish the structure-activity relationship (SAR) of the compounds, 3D-QSAR techniques such as Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) were used. The CoMFA (q 2 = 0.774, r 2 = 0.965, ONC = 6, and r p r e d 2 = 0.703) and CoMSIA (q 2 = 0.676, r 2 = 0.949, ONC = 6, and r p r e d 2 = 0.548) both models have shown reasonable external predictive activity, and contour maps revealed favorable and unfavorable substitutions for chemical group modifications. Based on the contour maps, we have designed forty new compounds, among which, seven compounds exhibited higher predictive activity (pIC50). Further, we conducted the MD study, ADME/Tox, and SA score prediction using the seven newly designed compounds. The combination of docking, MD, and 3D-QSAR studies helps to understand the coherence modification of existing molecules. Our study may provide valuable insight into the development of more potent ROCK1 inhibitors.

Synthesis of aminoquinazoline derivatives and their antiproliferative activities against melanoma cell line.

The synthesis of a novel series of aminoquinazoline derivatives 1a-r and their antiproliferative activities against A375 human melanoma cell line were described. Among them, six compounds showed superior antiproliferative activities to Sorafenib as a reference compound. In particular, the representative compound 1q bearing chromen-4-one moiety exhibited excellent antiproliferative activity (IC(50)=0.006 µM) and good selectivity over HS27 fibroblast cell line.

QM/MM based 3D QSAR models for potent B-Raf inhibitors.

Three dimensional (3D) quantitative structure-activity relationship studies of 37 B-Raf inhibitors, pyrazole-based derivatives, were performed. Based on the co-crystallized compound (PDB ID: 3D4Q), several alignment methods were utilized to derive reliable comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models. Receptor-guided alignment with quantum mechanics/molecular mechanics (QM/MM) minimization led to the best CoMFA model (q (2) = 0.624, r (2) = 0.959). With the same alignment, a statistically reliable CoMSIA model with steric, H-bond acceptor, and hydrophobic fields was also derived (q (2) = 0.590, r (2) = 0.922). Both models were validated with an external test set, which gave satisfactory predictive r (2) values of 0.926 and 0.878, respectively. Contour maps from CoMFA and CoMSIA models revealed important structural features responsible for increasing biological activity within the active site and explained the correlation between biological activity and receptor-ligand interactions. New fragments were identified as building blocks which can replace R1-3 groups through combinatorial screening methods. By combining these fragments a compound with a high bioactivity level prediction was found. These results can offer useful information for the design of new B-Raf inhibitors.

Structural studies of B-type Aurora kinase inhibitors using computational methods.

AIM: To characterize the structural features of quinazoline-based Aurora B inhibitors that influence its inhibitor activity. METHODS: Two geometrical methods, Method 1 and Method 2, were used to develop the 3D-QSAR models. The most active ligand was used as the template for the alignment of all the ligands in Method 1, and a conformer of the cocrystal ligand was used as the template for the alignment of all the ligands in Method 2. RESULTS: The models suggest that highly active ligands can be designed by varying the R1 substituent at position 7 of the quinazoline ring with positively charged, bulky, hydrophobic groups, while bulky and hydrophobic groups around the thiazole ring are desirable for higher activity. CONCLUSION: This study emphasizes that the bioactive conformer is rather different from the minima. The steric, electrostatic, and hydrophobic field effects contribute to its inhibitory activity.

Rational approach toward COVID-19 main protease inhibitors via molecular docking, molecular dynamics simulation and free energy calculation.

In the rapidly evolving coronavirus disease (COVID-19) pandemic, repurposing existing drugs and evaluating commercially available inhibitors against druggable targets of the virus could be an effective strategy to accelerate the drug discovery process. The 3C-Like proteinase (3CLpro) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified as an important drug target due to its role in viral replication. The lack of a potent 3CLpro inhibitor and the availability of the X-ray crystal structure of 3CLpro (PDB-ID 6LU7) motivated us to perform computational studies to identify commercially available potential inhibitors. A combination of modeling studies was performed to identify potential 3CLpro inhibitors from the protease inhibitor database MEROPS ( https://www.ebi.ac.uk/merops/index.shtml ). Binding energy evaluation identified key residues for inhibitor design. We found 15 potential 3CLpro inhibitors with higher binding affinity than that of an α-ketoamide inhibitor determined via X-ray structure. Among them, saquinavir and three other investigational drugs aclarubicin, TMC-310911, and faldaprevir could be suggested as potential 3CLpro inhibitors. We recommend further experimental investigation of these compounds.

Aminoquinoline derivatives with antiproliferative activity against melanoma cell line.

The synthesis of a novel series of aminoquinoline derivatives 1a-p and their antiproliferative activities against A375 human melanoma cell line were described. Most compounds showed superior antiproliferative activities to Sorafenib as a reference compound. Among them, quinolinyloxymethylphenyl compounds 1k and 1l exhibited potent activities (IC(50)=0.77 and 0.79microM, respectively) and excellent selectivity against melanoma and fibroblast cell lines.

Design, synthesis, screening, and molecular modeling study of a new series of ROS1 receptor tyrosine kinase inhibitors.

A series of rationally designed ROS1 tyrosine kinase inhibitors was synthesized and screened. Compound 12b has showed good potency with IC50 value of 209 nM, which is comparable with that of the reference lead compound 1. Molecular modeling studies have been performed, that is, a homology model for ROS1 was built, and the screened inhibitors were docked into its major identified binding site. The docked poses along with the activity data have revealed a group of the essential features for activity. Overall, simplification of the lead compound 1 into compound 12b has maintained the activity, while facilitated the synthetic advantages. A molecular interaction model for ROS1 kinase and inhibitors has been proposed.