Artificial intelligence based virtual screening study for competitive and allosteric inhibitors of the SARS-CoV-2 main protease

被引:3
作者
Charles, Ssemuyiga [1 ,2 ]
Edgar, Mulumba Pius [1 ]
Mahapatra, Rajani Kanta [1 ,3 ]
机构
[1] KIIT Deemed Univ, Sch Biotechnol, Bhubaneswar, Odisha, India
[2] Makerere Univ, Sch Biol Sci, Dept Microbiol Biotechnol & Plant Sci, Kampala, Uganda
[3] KIIT Deemed Univ, Sch Biotechnol, Campus 11, Bhubaneswar 751024, Odisha, India
关键词
Artificial intelligence; COVID-19; deep docking; molecular docking; molecular dynamics simulation; neural networks; SARS-CoV-2 main protease; RESPIRATORY SYNDROME-CORONAVIRUS; FORCE-FIELD; DOCKING; MECHANISM; DESIGN; DIMERIZATION; GENERATION; PREDICTION; MOLECULES; ACCURACY;
D O I
10.1080/07391102.2023.2188419
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
SARS-CoV-2 is a highly contagious and dangerous coronavirus that first appeared in late 2019 causing COVID-19, a pandemic of acute respiratory illnesses that is still a threat to health and the general public safety. We performed deep docking studies of 800 M unique compounds in both the active and allosteric sites of the SARS-COV-2 Main Protease (M-pro) and the 15 M and 13 M virtual hits obtained were further taken for conventional docking and molecular dynamic (MD) studies. The best XP Glide docking scores obtained were -14.242 and -12.059 kcal/mol by CHEMBL591669 and the highest binding affinities were -10.5 kcal/mol (from 444215) and -11.2 kcal/mol (from NPC95421) for active and allosteric sites, respectively. Some hits can bind both sites making them a great area of concern. Re-docking of 8 random allosteric complexes in the active site shows a significant reduction in docking scores with a t-test P value of 2.532 x 10(-11) at 95% confidence. Some specific interactions have higher elevations in docking scores. MD studies on 15 complexes show that single-ligand systems are stable as compared to double-ligand systems, and the allosteric binders identified are shown to modulate the active site binding as evidenced by the changes in the interaction patterns and stability of ligands and active site residues. When an allosteric complex was docked to the second monomer to check for homodimer formation, the validated homodimer could not be re-established, further supporting the potential of the identified allosteric binders. These findings could be important in developing novel therapeutics against SARS-CoV-2.Communicated by Ramaswamy H. Sarma
引用
收藏
页码:15286 / 15304
页数:19
相关论文
共 84 条
[1]   First con firmed detection of SARS-CoV-2 in untreated wastewater in Australia: A proof of concept for the wastewater surveillance of COVID-19 in the community [J].
Ahmed, Warish ;
Angel, Nicola ;
Edson, Janette ;
Bibby, Kyle ;
Bivins, Aaron ;
O'Brien, Jake W. ;
Choi, Phil M. ;
Kitajima, Masaaki ;
Simpson, Stuart L. ;
Li, Jiaying ;
Tscharke, Ben ;
Verhagen, Rory ;
Smith, Wendy J. M. ;
Zaugg, Julian ;
Dierens, Leanne ;
Hugenholtz, Philip ;
Thomas, Kevin, V ;
Mueller, Jochen F. .
SCIENCE OF THE TOTAL ENVIRONMENT, 2020, 728
[2]   Coronavirus main proteinase (3CLpro) structure:: Basis for design of anti-SARS drugs [J].
Anand, K ;
Ziebuhr, J ;
Wadhwani, P ;
Mesters, JR ;
Hilgenfeld, R .
SCIENCE, 2003, 300 (5626) :1763-1767
[3]  
[Anonymous], QPLD MAN GOOGL SEARC
[4]  
[Anonymous], 2022, COVID LIV COR STAT W
[5]  
[Anonymous], 2022, CURR ICTV TAX REL J
[6]  
Bauer P, 2022, GROMACS 2022.1 Manual, DOI [10.5281/zenodo.6451567, DOI 10.5281/ZENODO.6451567]
[7]   Applying Physics-Based Scoring to Calculate Free Energies of Binding for Single Amino Acid Mutations in Protein-Protein Complexes [J].
Beard, Hege ;
Cholleti, Anuradha ;
Pearlman, David ;
Sherman, Woody ;
Loving, Kathryn A. .
PLOS ONE, 2013, 8 (12)
[8]   Severe acute respiratory syndrome coronavirus 3C-like proteinase n terminus is indispensable for proteolytic activity but not for enzyme dimerization - Biochemical and thermodynamic investigation in conjunction with molecular dynamics simulations [J].
Chen, S ;
Chen, LL ;
Tan, JZ ;
Chen, J ;
Du, L ;
Sun, T ;
Shen, JH ;
Chen, KX ;
Jiang, HL ;
Shen, X .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (01) :164-173
[9]   Residues on the dimer interface of SARS coronavirus 3C-like protease: Dimer stability characterization and enzyme catalytic activity analysis [J].
Chen, Shuai ;
Zhang, Jian ;
Hu, Tiancen ;
Chen, Kaixian ;
Jiang, Hualiang ;
Shen, Xu .
JOURNAL OF BIOCHEMISTRY, 2008, 143 (04) :525-536
[10]   Liberation of SARS-CoV main protease from the viral polyprotein: N-terminal autocleavage does not depend on the mature dimerization mode [J].
Chen, Shuai ;
Jonas, Felix ;
Shen, Can ;
Higenfeld, Rolf .
PROTEIN & CELL, 2010, 1 (01) :59-74