title: In silico discovery of potential VEGFR-2 inhibitors from natural derivatives for anti-angiogenesis therapy.
abstract: Angiogenesis is the growth of new capillaries from existing blood vessels that supply oxygen and nutrients and provide gateways for immune surveillance. Abnormal vessel growth in term of excessive angiogenesis is a hallmark of cancer, inflammatory and eye diseases. VEGFR-2 (vascular endothelial growth factor receptor 2) dominating the process of angiogenesis has led to approval of therapeutic inhibitors and is becoming a promising target for anti-angiogenic drugs. Notwithstanding these successes, the clinical use of current VEGFR-2 blockers is more challenging than anticipated. Taking axitinib as a reference drug, in our study we found three potent VEGFR-2 inhibitors (ZINC08254217, ZINC08254138, and ZINC03838680) from natural derivatives. Each of the three inhibitors acquired a better grid score than axitinib (-62.11) when docked to VEGFR-2. Molecular dynamics simulations demonstrated that ZINC08254217- and ZINC08254138-VEGFR-2 complexes were more stable than axitinib. Similar to bind free energy for axitinib (-54.68 kcal/mol), such for ZINC03838680, ZINC08254217, and ZINC08254138 was -49.37, -43.32, and -32.73 kcal/mol respectively. These results suggested these three compounds could be candidate drugs against angiogenesis, with comparable VEGFR-2 binding affinity of axitinib. Hence findings in our study are able to provide valuable information on discovery of effective anti-angiogenesis therapy.
authors.affiliation: College of Life Sciences and Key Laboratory for Bio-Resources of Ministry of Education, Sichuan University, Chengdu 610064, China. lijing_22@aliyun.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: College of Life Sciences and Key Laboratory for Bio-Resources of Ministry of Education, Sichuan University, Chengdu 610064, China. zhnanx@live.com.
authors.forename: Nan
authors.initials: N
authors.lastname: Zhou
authors.affiliation: College of Life Sciences and Key Laboratory for Bio-Resources of Ministry of Education, Sichuan University, Chengdu 610064, China. luokun9527@gmail.com.
authors.forename: Kun
authors.initials: K
authors.lastname: Luo
authors.affiliation: College of Life Sciences and Key Laboratory for Bio-Resources of Ministry of Education, Sichuan University, Chengdu 610064, China. zhgwe2010@163.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: College of Life Sciences and Key Laboratory for Bio-Resources of Ministry of Education, Sichuan University, Chengdu 610064, China. lixinruswxxx@163.com.
authors.forename: Xinru
authors.initials: X
authors.lastname: Li
authors.affiliation: College of Life Sciences and Key Laboratory for Bio-Resources of Ministry of Education, Sichuan University, Chengdu 610064, China. wuchuanfang@gmail.com.
authors.forename: Chuanfang
authors.initials: C
authors.lastname: Wu
authors.affiliation: College of Life Sciences and Key Laboratory for Bio-Resources of Ministry of Education, Sichuan University, Chengdu 610064, China. baojinku@scu.edu.cn.
authors.forename: Jinku
authors.initials: J
authors.lastname: Bao
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000378:metabolism; D000077784:Axitinib; D001665:Binding Sites; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism; D007191:Indazoles / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D011812:Quinuclidines / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics; D014230:Triazoles / Q000737:chemistry* / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D007093:Imidazoles; D007191:Indazoles; D011812:Quinuclidines; D014230:Triazoles; C000598183:ZINC03838680; C000598182:ZINC08254138; C000598181:ZINC08254217; D000077784:Axitinib; D040301:Vascular Endothelial Growth Factor Receptor-2