Unraveling structural requirements of amino-pyrimidine T790M/L858R double mutant EGFR inhibitors: 2D and 3D QSAR study.

EGFR is an important drug target in cancer. However, the ineffectiveness of first generation inhibitors due to the occurrence of a secondary mutation (T790M) results in the relapse of the disease. Identification of reversible inhibitors against T790M/L858R double mutants (TMLR) thus is a foremost requirement. In this study, various 2 D and 3 D Quantitative Structure-Activity Relationship models were built for amino-pyrimidine compounds with their known biological activity against TMLR mutants. The model developed using multiple linear regression statistical method via stepwise forward-backward variable selection technique showed the best results in terms of internal and external predictivity. The 2D-QSAR model indicated that the presence of electronegative atom, H-bond donors, moderate slogp, count of number of N atoms separated from O (T_N_O_4), 4pathClusterCount and number of S atom connected with two single bonds (SssSE-index), is required for increasing the inhibitory potential of compounds. Also, the 3D-QSAR model suggested that electronegative group at certain positions along with the presence of bulky groups is beneficial for good inhibition activity of the compounds. Thus, the QSAR models developed in the present work can be used for predicting the TMLR bioactivity of a new series of amino-pyrimidine derivatives. To the best of the author's knowledge, this is the first study which deals with the development of 2 D and 3D-QSAR models for double mutant TMLR inhibitors.

Exploring binding stability of hydroxy-3-(4-hydroxyphenyl)-5-(4-nitrophenyl)-5,5a,7,8,9,9a-hexahydrothiazolo[2,3-b] quinazolin-6-one with T790M/L858R EGFR-TKD.

Cancer causes innumerable deaths every year globally. Breast cancer and non-small cell lung carcinoma are the most prevalent worldwide. EGFR-TKD is a neoplastic survival therapeutic target in a wide array of carcinoma cells. Various non-specific tyrosine kinase inhibitors lead to hyperphosphorylation and overexpression of EGFR-TKD and further mutations recognise deletion of exon 19. In this work, we study the binding affinity, binding stability, and strength of hydroxy-3-(4-hydroxyphenyl)-5-(4-nitrophenyl)-5,5a,7,8,9,9a-hexahydrothiazolo[2,3-b] quinazolin-6-one with TMLR mutated EGFR-TKD (T790M/L858R). The collective motions, residual mobility, and flexibility of TMLR mutated EGFR-TKD bound with reference and title molecule were calculated by principal component analysis. The meta-state conformations of both the simulated complexes were determined by Gibb's energy landscape analysis. The binding affinity exhibited by thiazolo-[2,3-b] quinazolinone and the reference molecule was found to be -7.95 ± 0.088 Kcal/mol and -9.13 ± 0.018 kcal/mol with TMLR mutated EGFR-TKD. The alignment of both the docked complexes was done by blosum40 matrix. Similar spatial orientations were exhibited by the synthesised ligand in the binding pocket of TMLR mutated EGFR-TKD, corresponding to the reference ligand. The ligand stability was computed for 100 ns. In addition, the radius of gyration, solvent accessible surface area, hydrogen bonds formed was calculated. The average ΔGbind of thiazolo-[2,3-b] quinazolinone was -41.212 ± 0.834 kJ/mol and for reference ligand -71.938 ± 0.367 kJ/mol, calculated by MM-PBSA. ADMET analysis concludes thiazolo-[2,3-b] quinazolinone derivative is safe. Further research work is encouraged to determine the efficacy of thiazolo-[2,3-b] quinazolinone against in vivo models.Communicated by Ramaswamy H. Sarma.

From cold-blooded reptiles to embryological remnants: Persistent myocardial sinusoids.

In nature, basically 2 types of myocardial vascular patterns exist: the sinusoidal and the coronary type. In the sinusoidal type, the sinusoid is completely fed by blood coming directly from the ventricle through a spongy sinusoidal network. This pattern is found in cold-blooded animals and in the early embryologic development of human (warm-blooded) hearts. A 61-year-old man with atrial fibrillation developed severe tachymyopathy with a severely reduced left-ventricular ejection fraction (LVEF) of 20%. The patient had no history of prior heart surgery or other cardiac interventions. He was referred for a computed tomography (CT) scan for assessment of pulmonary vein anatomy prior to their isolation. Incidentally, a focal myocardial defect of the midventricular infero-septal wall with tail-like extension into the right ventricular cavity was detected. In a cardiac magnetic resonance (CMR) scan there was no evidence of a myocardial infarction or fibrosis. In the absence of a ventricular septal defect by CT, CMR and echocardiography the diagnosis of a persistent myocardial sinusoid was evident. In this case, we used state-of-the art methods for pathology visualization, illustrating the effectiveness of CT and CMR in the precise detection and differential diagnosis of myocardial anomalies including a multi-coloured 3D-printed model that may further enhance visuospatial appreciation of those anomalies.

In-silico evidences for binding of Glucokinase activators to EGFR C797S to overcome EGFR resistance obstacle with mutant-selective allosteric inhibition.

The tyrosine kinase inhibitors (TKI) against epidermal growth factor receptor (EGFR) are generally utilized as a part of patients with non-small cell lung carcinoma (NSCLC). However, EGFR T790M mutation results in resistance to most clinically available EGFR TKIs. Third-generation EGFR TKIs against the T790M mutation has been in active clinical development to triumph the resistance problem; they covalently bind with conserved Cys797 inside the EGFR active site, offering both potency and kinase-selectivity. Third generation drugs target C797, which makes the C797S resistance mutation more subtle. EGFR C797S mutation was accounted to be a main mechanism of resistance to the third-generation inhibitors. The C797S mutation gives off an impression of being an ideal target for conquering the acquired resistance to the third generation inhibitors. We have performed structure based-virtual screening strategies for binding of glucokinase activator to EGFR C797S, which can overcome EGFR resistance impediment with mutant-selective allosteric inhibition towards all kinds of mutant EGFR (T790M, L858R, TMLR) and WT EGFR. The final filter of Lipinski's Rule of Five, Jargan's Rule of Three and in silico ADME predictions gave 23 hits, which conform to Lipinski's rule and Jorgensen's rule and all their pharmacokinetic parameters are inside the appropriate range characterized for human use, in this manner demonstrating their potential as a drug-like molecule.

Insight into Discovery of Next Generation Reversible TMLR Inhibitors Targeting EGFR Activating and Drug Resistant T790M Mutants.

BACKGROUND: Epidermal growth factor receptor (EGFR) is a well-recognised drug target exploited for treating non-small cell lung cancer (NSCLC). Gefitinib and erlotinib are first generation clinically employed inhibitors used against EGFR activating mutants. However, during course of treatment these inhibitors become ineffective due to the emergence of an acquired secondary mutation. Subsequently, in order to overcome non-responsiveness second and third generation inhibitors were designed having covalent bond and irreversible mode of action. However, these inhibitors were shown to be toxic. This led to the discovery of lead candidates with completely different mode of action and therapeutic efficacy. OBJECTIVE: We have reviewed the recent efforts undertaken by researchers in discovering newer noncovalent reversible next generation inhibitors for treating NSCLC. METHODS: We first studied the optimization steps and pharmacokinetic variables of the synthesised molecules. We also analysed bonds and interactions using PDB X-ray crystal structures as well as scaffold and selectivity analysis was undertaken. RESULTS: We identified that ligand lipophilic efficiency driven potency is a preferable optimisation parameter for maintaining drug likeliness of the molecule. Also, few h-bonds were recognised as major players in affecting the binding of compound. The scaffold analysis revealed that ligand molecules with pyrimidine core exhibit higher inhibitory activity against TMLR, as well as higher selectivity with respect to other kinases. CONCLUSION: Next generation reversible inhibitors exhibited unique binding mode and were found to occupy three major pockets (ribose pocket, back pocket and hinge region), which is critical for increasing the selectivity of the compound against TMLR mutants.