• Something wrong with this record ?

Genomic and computational-aided integrative drug repositioning strategy for EGFR and ROS1 mutated NSCLC

V. Tripathi, A. Khare, D. Shukla, S. Bharadwaj, N. Kirtipal, V. Ranjan

. 2024 ; 139 (-) : 112682. [pub] 20240718

Language English Country Netherlands

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc24018837

Non-small cell lung cancer (NSCLC) has been marked as the major cause of death in lung cancer patients. Due to tumor heterogeneity, mutation burden, and emerging resistance against the available therapies in NSCLC, it has been posing potential challenges in the therapy development. Hence, identification of cancer-driving mutations and their effective inhibition have been advocated as a potential approach in NSCLC treatment. Thereof, this study aims to employ the genomic and computational-aided integrative drug repositioning strategy to identify the potential mutations in the selected molecular targets and repurpose FDA-approved drugs against them. Accordingly, molecular targets and their mutations, i.e., EGFR (V843L, L858R, L861Q, and P1019L) and ROS1 (G1969E, F2046Y, Y2092C, and V2144I), were identified based on TCGA dataset analysis. Following, virtual screening and redocking analysis, Elbasvir, Ledipasvir, and Lomitapide drugs for EGFR mutants (>-10.8 kcal/mol) while Indinavir, Ledipasvir, Lomitapide, Monteleukast, and Isavuconazonium for ROS1 mutants (>-8.8 kcal/mol) were found as putative inhibitors. Furthermore, classical molecular dynamics simulation and endpoint binding energy calculation support the considerable stability of the selected docked complexes aided by substantial hydrogen bonding and hydrophobic interactions in comparison to the respective control complexes. Conclusively, the repositioned FDA-approved drugs might be beneficial alone or in synergy to overcome acquired resistance to EGFR and ROS1-positive lung cancers.

References provided by Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc24018837
003      
CZ-PrNML
005      
20241024111118.0
007      
ta
008      
241015e20240718ne f 000 0|eng||
009      
AR
024    7_
$a 10.1016/j.intimp.2024.112682 $2 doi
035    __
$a (PubMed)39029228
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a ne
100    1_
$a Tripathi, Varsha $u Department of Biochemistry, Dr. Ram Manohar Lohia Avadh University Ayodhya, Uttar Pradesh, India
245    10
$a Genomic and computational-aided integrative drug repositioning strategy for EGFR and ROS1 mutated NSCLC / $c V. Tripathi, A. Khare, D. Shukla, S. Bharadwaj, N. Kirtipal, V. Ranjan
520    9_
$a Non-small cell lung cancer (NSCLC) has been marked as the major cause of death in lung cancer patients. Due to tumor heterogeneity, mutation burden, and emerging resistance against the available therapies in NSCLC, it has been posing potential challenges in the therapy development. Hence, identification of cancer-driving mutations and their effective inhibition have been advocated as a potential approach in NSCLC treatment. Thereof, this study aims to employ the genomic and computational-aided integrative drug repositioning strategy to identify the potential mutations in the selected molecular targets and repurpose FDA-approved drugs against them. Accordingly, molecular targets and their mutations, i.e., EGFR (V843L, L858R, L861Q, and P1019L) and ROS1 (G1969E, F2046Y, Y2092C, and V2144I), were identified based on TCGA dataset analysis. Following, virtual screening and redocking analysis, Elbasvir, Ledipasvir, and Lomitapide drugs for EGFR mutants (>-10.8 kcal/mol) while Indinavir, Ledipasvir, Lomitapide, Monteleukast, and Isavuconazonium for ROS1 mutants (>-8.8 kcal/mol) were found as putative inhibitors. Furthermore, classical molecular dynamics simulation and endpoint binding energy calculation support the considerable stability of the selected docked complexes aided by substantial hydrogen bonding and hydrophobic interactions in comparison to the respective control complexes. Conclusively, the repositioned FDA-approved drugs might be beneficial alone or in synergy to overcome acquired resistance to EGFR and ROS1-positive lung cancers.
650    _2
$a lidé $7 D006801
650    12
$a přehodnocení terapeutických indikací léčivého přípravku $7 D058492
650    12
$a nemalobuněčný karcinom plic $x farmakoterapie $x genetika $7 D002289
650    12
$a nádory plic $x genetika $x farmakoterapie $7 D008175
650    12
$a erbB receptory $x genetika $x antagonisté a inhibitory $7 D066246
650    12
$a tyrosinkinasy $x genetika $x antagonisté a inhibitory $7 D011505
650    12
$a mutace $7 D009154
650    12
$a protoonkogenní proteiny $x genetika $7 D011518
650    12
$a protinádorové látky $x farmakologie $x terapeutické užití $7 D000970
650    _2
$a simulace molekulového dockingu $7 D062105
650    _2
$a inhibitory proteinkinas $x farmakologie $x terapeutické užití $7 D047428
650    _2
$a genomika $x metody $7 D023281
655    _2
$a časopisecké články $7 D016428
700    1_
$a Khare, Aishwarya $u Department of Biochemistry, Dr. Ram Manohar Lohia Avadh University Ayodhya, Uttar Pradesh, India
700    1_
$a Shukla, Divyanshi $u Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India; Computational Chemistry & Drug Discovery Division, Quanta Calculus, Greater Noida, India. Electronic address: divyanshi.quanta@gmail.com
700    1_
$a Bharadwaj, Shiv $u Laboratory of Ligand Engineering, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV Research Center, Průmyslová 595, 252 50 Vestec, Czech Republic. Electronic address: shiv.bharadwaj@ibt.cas.cz
700    1_
$a Kirtipal, Nikhil $u School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea. Electronic address: nkirtipal5@gist.ac.kr
700    1_
$a Ranjan, Vandana $u Department of Biochemistry, Dr. Ram Manohar Lohia Avadh University Ayodhya, Uttar Pradesh, India. Electronic address: Vandanaranjan@rmlau.ac.in
773    0_
$w MED00006034 $t International immunopharmacology $x 1878-1705 $g Roč. 139 (20240718), s. 112682
856    41
$u https://pubmed.ncbi.nlm.nih.gov/39029228 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y - $z 0
990    __
$a 20241015 $b ABA008
991    __
$a 20241024111112 $b ABA008
999    __
$a ok $b bmc $g 2201605 $s 1230810
BAS    __
$a 3
BAS    __
$a PreBMC-MEDLINE
BMC    __
$a 2024 $b 139 $c - $d 112682 $e 20240718 $i 1878-1705 $m International immunopharmacology $n Int Immunopharmacol $x MED00006034
LZP    __
$a Pubmed-20241015

Find record

Citation metrics

Archiving options