Ensemble docking and molecular dynamics identify knoevenagel curcumin derivatives with potent anti-EGFR activity.
Epidermal growth factor receptor tyrosine kinase (EGFR-TK) is an attractive target for cancer therapy. Despite a number of effective EGFR inhibitors that are constantly expanding and different methods being employed to obtain novel compounds, the search for newer EGFR inhibitors is still a major scientific challenge. In the present study, a molecular docking and molecular dynamics investigation has been carried out with an ensemble of EGFR-TK structures against a synthetically feasible library of curcumin analogs to discover potent EGFR inhibitors. To resolve protein flexibility issue we have utilized 5 EGFR wild type crystal structures during docking as this gives improved possibility of identifying an active compound as compared to using a single crystal structure. We then identified five curcumin analogs representing different scaffolds that can serve as lead molecules. Finally, the 5 ns molecular dynamics simulation shows that knoevenagel condensate of curcumin specifically C29 and C30 can be used as starting blocks for developing effective leads capable of inhibiting EGFR.
Bioinformatics Division, Institute of Cytology and Preventive Oncology, I-7 Sector-39, Noida 201301, India; Department of Bio & Nano Technology, Guru Jambheshwar University Science & Technology, Hisar, India.
Inderjit S
IS
Yadav
Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab, India.
Prajwal P
PP
Nandekar
Shambhavi
S
Srivastavaa
Bioinformatics Division, Institute of Cytology and Preventive Oncology, I-7 Sector-39, Noida 201301, India.
Shambhavi
S
Shrivastava
Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab, India.
Abhay
A
Sangamwar
Department of Bio & Nano Technology, Guru Jambheshwar University Science & Technology, Hisar, India.
Ashok
A
Chaudhury
Bioinformatics Division, Institute of Cytology and Preventive Oncology, I-7 Sector-39, Noida 201301, India. Electronic address: smagarwal@yahoo.com.
Subhash Mohan
SM
Agarwal
D000970:Antineoplastic Agents / Q000494:pharmacology; D020134:Catalytic Domain / Q000235:genetics; D018360:Crystallography, X-Ray; D003474:Curcumin / Q000031:analogs & derivatives* / Q000378:metabolism*; D055808:Drug Discovery; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000648:ultrastructure; D006801:Humans; D062105:Molecular Docking Simulation / Q000379:methods*; D056004:Molecular Dynamics Simulation; D009369:Neoplasms / Q000188:drug therapy; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; C512478:EGFR protein, human; D066246:ErbB Receptors; D003474:Curcumin
Curcumin; EGFR; Ensemble docking; Molecular dynamics; Tyrosine kinase