Search

A new lead compound has been designed as an antiangiogenic EGFR inhibitor that has the pharmacophoric characteristics to bind with the catalytic pocket of EGFR protein. The designed lead compound is a (para-chloro)acetamide derivative of the alkaloid, theobromine, ( T-1-PCPA ). At first, we started with deep density functional theory (DFT) calculations for T-1-PCPA to confirm and optimize its 3D structure. Additionally, the DFT studies identified the electrostatic potential, global reactive indices and total density of states expecting a high level of reactivity for T-1-PCPA . Secondly, the affinity of T-1-PCPA to bind and inhibit the EGFR protein was studied and confirmed through detailed structure-based computational studies including the molecular docking against EGFR WT and EGFR T790M , Molecular dynamics (MD) over 100 ns, MM-GPSA and PLIP experiments. Before the preparation, the computational ADME and toxicity profiles of T-1-PCPA have been investigated and its safety and the general drug-likeness predicted. Accordingly, T-1-PCPA was semi-synthesized to scrutinize the proposed design and the obtained in silico results. Interestingly, T-1-PCPA inhibited in vitro EGFR WT with an IC 50 value of 25.35 nM, comparing that of erlotinib (5.90 nM). Additionally, T-1-PCPA inhibited the growth of A549 and HCT-116 malignant cell lines with IC 50 values of 31.74 and 20.40 µM, respectively, comparing erlotinib that expressed IC 50 values of 6.73 and 16.35 µM, respectively.

As an extension of our research against COVID-19, a multiphase in silico approach was applied in the selection of the three most common inhibitors (Glycyrrhizoflavone ( 76 ), Arctigenin ( 94 ) , and Thiangazole ( 298 )) against papain-like protease, PLpro (PDB ID: 4OW0), among 310 metabolites of natural origin. All compounds of the exam set were reported as antivirals. The structural similarity between the examined compound set and S88 , the co-crystallized ligand of PLpro, was examined through structural similarity and fingerprint studies. The two experiments pointed to Brevicollin ( 28 ), Cryptopleurine ( 41 ), Columbamine ( 46 ), Palmatine ( 47 ), Glycyrrhizoflavone ( 76 ), Licochalcone A ( 87 ), Arctigenin ( 94 ), Termilignan ( 98 ), Anolignan B ( 99 ), 4,5-dihydroxy-6″-deoxybromotopsentin ( 192 ), Dercitin ( 193 ), Tryptanthrin ( 200 ), 6-Cyano-5-methoxy-12-methylindolo [2, 3A] carbazole ( 211 ), Thiangazole ( 298 ), and Phenoxan ( 300 ). The binding ability against PLpro was screened through molecular docking, disclosing the favorable binding modes of six metabolites. ADMET studies expected molecules 28 , 76 , 94 , 200 , and 298 as the most favorable metabolites. Then, molecules 76 , 94 , and 298 were chosen through in silico toxicity studies. Finally, DFT studies were carried out on glycyrrhizoflavone ( 76 ) and indicated a high level of similarity in the molecular orbital analysis. The obtained data can be used in further in vitro and in vivo studies to examine and confirm the inhibitory effect of the filtered metabolites against PLpro and SARS-CoV-2.