Targeting Caspase 8: Using Structural and Ligand-Based Approaches to Identify Potential Leads for the Treatment of Multi-Neurodegenerative Diseases

被引:10
作者
Ahmad, Khurshid [1 ]
Balaramnavar, Vishal M. [2 ]
Chaturvedi, Navaneet [3 ]
Khan, Saif [4 ]
Haque, Shafiul [5 ]
Lee, Yong-Ho [6 ]
Choi, Inho [1 ]
机构
[1] Yeungnam Univ, Dept Med Biotechnol, Gyongsan 38541, South Korea
[2] GIPER, Dept Pharmaceut Chem, Kashipur 44713, Uttarakhand, India
[3] Univ Informat Sci & Technol St Paul Apostle, Ohrid 6000, North Macedonia
[4] Hail Univ, Coll Dent, Hail 2440, Saudi Arabia
[5] Jazan Univ, Coll Nursing & Allied Hlth Sci, Res & Sci Studies Unit, Jazan 45142, Saudi Arabia
[6] Daegu Catholic Univ, Dept Biomed Sci, Gyongsan 38430, South Korea
基金
新加坡国家研究基金会;
关键词
caspase; 8; ligand; pharmacophore; neurodegeneration; virtual screening; ALZHEIMER-DISEASE; ACTIVATION; INHIBITORS; APOPTOSIS; PROTEIN; SPECIFICITY; MICROGLIA; DOCKING; IDENTIFICATION; NECROPTOSIS;
D O I
10.3390/molecules24091827
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Caspase 8 is a central player in the apoptotic cell death pathway and is also essential for cytokine processing. The critical role of this protease in cell death pathways has generated research interest because its activation has also been linked with neural cell death. Thus, blocking the activity of caspase 8 is considered a potential therapy for neurodegenerative diseases. To extend the repertoire of caspase 8 inhibitors, we employed several computational approaches to identify potential caspase 8 inhibitors. Based on the structural information of reported inhibitors, we designed several individual and consensus pharmacophore models and then screened the ZINC database, which contains 105,480 compounds. Screening generated 5332 candidates, but after applying stringent criteria only two candidate compounds, ZINC19370490 and ZINC04534268, were evaluated by molecular dynamics simulations and subjected to Molecular Mechanics/Poisson Boltzmann Surface Area (MM-PBSA) analysis. These compounds were stable throughout simulations and interacted with targeted protein by forming hydrogen and van der Waal bonds. MM-PBSA analysis showed that these compounds were comparable or better than reported caspase 8 inhibitors. Furthermore, their physical properties were found to be acceptable, and they are non-toxic according to the ADMET online server. We suggest that the inhibitory efficacies of ZINC19370490 and ZINC04534268 be subjected to experimental validation.
引用
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页数:11
相关论文
共 47 条
[1]   Commonalities in Biological Pathways, Genetics, and Cellular Mechanism between Alzheimer Disease and Other Neurodegenerative Diseases: An In Silico-Updated Overview [J].
Ahmad, Khurshid ;
Baig, Mohammad Hassan ;
Mushtaq, Gohar ;
Kamal, Mohammad Amjad ;
Greig, Nigel H. ;
Choi, Inho .
CURRENT ALZHEIMER RESEARCH, 2017, 14 (11) :1190-1197
[2]   Identification of Potent Caspase-3 Inhibitors for Treatment of Multi-Neurodegenerative Diseases Using Pharmacophore Modeling and Docking Approaches [J].
Ahmad, Khurshid ;
Balaramnavar, Vishal M. ;
Baig, Mohammad H. ;
Srivastava, Ashwini K. ;
Khan, Saif ;
Kamal, Mohammad A. .
CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS, 2014, 13 (08) :1346-1353
[3]   Structure based molecular inhibition of Caspase-8 for treatment of multi-neurodegenerative diseases using known natural compounds [J].
Ahmad, Khurshid ;
Khan, Saif ;
Adil, Mohd ;
Saeed, Mohd ;
Srivastava, Ashwini Kumar .
BIOINFORMATION, 2014, 10 (04) :191-195
[4]   Computer Aided Drug Design: Success and Limitations [J].
Baig, Mohammad Hassan ;
Ahmad, Khurshid ;
Roy, Sudeep ;
Ashraf, Jalaluddin Mohammad ;
Adil, Mohd ;
Siddiqui, Mohammad Haris ;
Khan, Saif ;
Kamal, Mohammad Amjad ;
Provaznik, Ivo ;
Choi, Inho .
CURRENT PHARMACEUTICAL DESIGN, 2016, 22 (05) :572-581
[5]   Identification of novel PTP1B inhibitors by pharmacophore based virtual screening, scaffold hopping and docking [J].
Balaramnavar, Vishal M. ;
Srivastava, Rohit ;
Rahuja, Neha ;
Gupta, Swati ;
Rawat, Arun K. ;
Varshney, Salil ;
Chandasana, Hardik ;
Chhonker, Yashpal S. ;
Doharey, Pawan Kumar ;
Kumar, Santosh ;
Gautam, Sudeep ;
Srivastava, Swayam Prakash ;
Bhatta, Rabi Sankar ;
Saxena, Jitendra Kumar ;
Gaikwad, Anil Nilkanth ;
Srivastava, Arvind K. ;
Saxena, Anil K. .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2014, 87 :578-594
[6]   Commonly used caspase inhibitors designed based on substrate specificity profiles lack selectivity [J].
Berger, Alicia B. ;
Sexton, Kelly B. ;
Bogyo, Matthew .
CELL RESEARCH, 2006, 16 (12) :961-963
[7]   Microglia-mediated neurotoxicity: uncovering the molecular mechanisms [J].
Block, Michelle L. ;
Zecca, Luigi ;
Hong, Jau-Shyong .
NATURE REVIEWS NEUROSCIENCE, 2007, 8 (01) :57-69
[8]   CHARMM - A PROGRAM FOR MACROMOLECULAR ENERGY, MINIMIZATION, AND DYNAMICS CALCULATIONS [J].
BROOKS, BR ;
BRUCCOLERI, RE ;
OLAFSON, BD ;
STATES, DJ ;
SWAMINATHAN, S ;
KARPLUS, M .
JOURNAL OF COMPUTATIONAL CHEMISTRY, 1983, 4 (02) :187-217
[9]   Caspase signalling controls microglia activation and neurotoxicity [J].
Burguillos, Miguel A. ;
Deierborg, Tomas ;
Kavanagh, Edel ;
Persson, Annette ;
Hajji, Nabil ;
Garcia-Quintanilla, Albert ;
Cano, Josefina ;
Brundin, Patrik ;
Englund, Elisabet ;
Venero, Jose L. ;
Joseph, Bertrand .
NATURE, 2011, 472 (7343) :319-U214
[10]   SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules [J].
Daina, Antoine ;
Michielin, Olivier ;
Zoete, Vincent .
SCIENTIFIC REPORTS, 2017, 7