Molecular Docking studies of N-Methyl- 2, 3 -Disubstituted Quinazolin-4-Ones Scaffold

In recent days, synthesis of anticancer molecules having both low adverse effects and specific protein targeting are seldom. Synthesis of anticancer molecules having both low adverse effects and specific protein targeting is challenging. The main objective of our study was to develop molecules that can target activated protein kinase P38 alpha and activin receptor (ALK2) kinase for treating carcinoma. P38 alpha is involved in cell differentiation, apoptosis, and autophagy.Activin receptor (ALK2) kinase is responsible for mutations of cancerous cells. The synthesis of N-Methyl - 2, 3 -Disubstituted Quinazolin-4-Ones was carried out by refluxing of 1-methyl-2-(pyridinyl)-1,2-dihydro-4H-3,1-benzoxazin-4-one with 4-substituted phenyl-1,3-thiazol-2-amines. The molecular docking of 1-methyl-3-(4-substituted phenyl-1,3-thiazol-2-yl)2-(pyridin-3-yl)-2,3-dihydroquinazolin-4(1H)-one (5Da1-5Dk11) and 1-methyl-3-(4-substituted phenyl- 1,3-thiazol-2-yl)-2-(pyridin-4-yl)-2,3dihydroquinazolin-4(1H)-one (5Ea1-5Ek11) derivatives were carried out using Schrodinger Glide (version 2020_1) software. Twenty-two quinazoline-4-one derivatives were docked into selective P38 alpha and ACVR1 (ALK2) kinase with PDB code 3GC7, 6GI6. Based on the docking score, comparison between quinazolin-4-one derivatives, co-crystallized Ligands interaction was evaluated using 5-Fluorouracil as standard. Best activity was found in compounds 5Df6, 5Dd4, 5Ed4 and 5Ef6 with ACVR1 (ALK2) kinase with score of -8.223, -7.936, -8.123, 7.907 and 5Df6, 5Dh8, 5Eb2 and 5Ee5 with P38alpha with score of -7.19, -7.027, -6.698, -6.789 Kcal/mol against enzymes responsible for treatment for cancer compare with reference drug score -5.765 and -6.195. This study will help in the design and development of a drug that gives room for the synthesis of a new selective ACVR1 (ALK2) kinase and P38alpha enzyme inhibitor with predetermined affinity and activity of the compound.