Sudeep Roy1, Akhil Kumar2, Mohd Hassan Baig3, Michal Masařík4, Ivo Provazník5. 1. Department of Biomedical Engineering, Faculty of Electrical Engineering and Communication, Brno University of Technology Technická 12, 61200 Brno, Czech Republic. Electronic address: roy@feec.vutbr.cz. 2. Biotechnology Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, India. Electronic address: akhil2687@gmail.com. 3. School of Biotechnology, Yeungnam University, Gyeongsan 712749, Republic of Korea. Electronic address: mohdhassanbaig@gmail.com. 4. Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Bld. A18, 625 00 Brno, Czech Republic. Electronic address: masarik@med.muni.cz. 5. International Clinical Research Center - Center of Biomedical Engineering, St. Anne's University Hospital Brno and Department of Biomedical Engineering, FEEC, Brno University of Technology, Brno, Czech Republic. Electronic address: ivo.provaznik@fnusa.cz.
Abstract
MOTIVATION: Metallothionein-III (MT-III) displays neuro-inhibitory activity and is involved in the repair of neuronal damage. An altered expression level of MT-III suggests that it could be a mitigating factor in Alzheimer's disease (AD) neuronal dysfunction. Currently there are limited marketed drugs available against MT-III. The inhibitors are mostly pseudo-peptide based with limited ADMET. In our present study, available database InterBioScreen (natural compounds) was screened out for MT-III. Pharmacodynamics and pharmacokinetic studies were performed. Molecular docking and simulations of top hit molecules were performed to study complex stability. RESULTS: Study reveals potent selective molecules that interact and form hydrogen bonds with amino acids Ser-6 and Lys-22 are common to established melatonin inhibitors for MT-III. These include DMHMIO, MCA B and s27533 derivatives. The ADMET profiling was better with comparable interaction energy values. It includes properties like blood brain barrier, hepatotoxicity, druggability, mutagenicity and carcinogenicity. Molecular dynamics studies were performed to validate our findings.
MOTIVATION:Metallothionein-III (MT-III) displays neuro-inhibitory activity and is involved in the repair of neuronal damage. An altered expression level of MT-III suggests that it could be a mitigating factor in Alzheimer's disease (AD) neuronal dysfunction. Currently there are limited marketed drugs available against MT-III. The inhibitors are mostly pseudo-peptide based with limited ADMET. In our present study, available database InterBioScreen (natural compounds) was screened out for MT-III. Pharmacodynamics and pharmacokinetic studies were performed. Molecular docking and simulations of top hit molecules were performed to study complex stability. RESULTS: Study reveals potent selective molecules that interact and form hydrogen bonds with amino acids Ser-6 and Lys-22 are common to established melatonin inhibitors for MT-III. These include DMHMIO, MCA B and s27533 derivatives. The ADMET profiling was better with comparable interaction energy values. It includes properties like blood brain barrier, hepatotoxicity, druggability, mutagenicity and carcinogenicity. Molecular dynamics studies were performed to validate our findings.
Authors: Sudeep Roy; Jaromir Gumulec; Akhil Kumar; Martina Raudenska; Mohd Hassan Baig; Hana Polanska; Jan Balvan; Mansi Gupta; Petr Babula; Jan Odstrčilík; Inho Choi; Ivo Provaznik; Michal Masarik Journal: Brain Behav Date: 2017-08-15 Impact factor: 2.708
Authors: Katarina Nikolic; Lazaros Mavridis; Teodora Djikic; Jelica Vucicevic; Danica Agbaba; Kemal Yelekci; John B O Mitchell Journal: Front Neurosci Date: 2016-06-10 Impact factor: 4.677