Impact of compound mutations I1171N + F1174I and I1171N + L1198H on the structure of ALK in NSCLC pathogenesis: atomistic insights

Salifu, Elliasu Y.; Issahaku, Abdul Rashid; Soliman, Mahmoud E. S.

doi:10.1080/07391102.2022.2072390

Cited by 6 publications

(12 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, molecular dynamic simulations was used to unveil the stability and flexibility of the selected ligands against the two fatty acid targets (Salifu et al, 2022). The cα atoms of the protein-ligand complexes were used to calculate the RMSD of the system that confirm low deviation of the system (Salifu et al, 2022), (Abdullahi et al, 2018). Generally, the acceptable threshold for an average change in RMSD of the protein-ligand complex 1-3Å (Ramírez and Caballero, 2018).…”

Section: Discussionmentioning

confidence: 99%

In silico identification of potential inhibitors of acyl carrier protein reductase and acetyl CoA carboxylase of Plasmodium falciparum in antimalarial therapy

Salifu¹,

Abugri²,

Rashid³

et al. 2023

Front. Drug Discov.

Self Cite

View full text Add to dashboard Cite

Malaria caused by Plasmodium falciparum, remains one of the most fatal parasitic diseases that has affected nearly a third of the world’s population. The major impediment to the treatment of malaria is the emergence of resistance of the P. falciparum parasite to current anti-malaria therapeutics such as Artemisinin (ART)-based combination therapy (ACT). This has resulted in countless efforts to develop novel therapeutics that will counter this resistance with the aim to control and eradicate the disease. The application of in silico modelling techniques has gained a lot of recognition in antimalarial research in recent times through the identification of biological components of the parasite for rational drug design. In this study we employed various in silico techniques such as the Virtual screening, molecular docking and molecular dynamic simulations to identify potential new inhibitors of biotin acetyl-coenzyme A (CoA) carboxylase and enoyl-acyl carrier reductase, two enzyme targets that play a crucial role in fatty acid synthesis in the Plasmodium parasite. Initially, nine hit compounds were identified for each of the two enzymes from the ZINCPharmer database. Subsequently, all hit compounds bind favourably to the active sites of the two enzymes as well as show excellent pharmacokinetic properties. Three 3) of the hits for the biotin acetyl-coenzyme A (CoA) carboxylase and six 6) of the enoyl-acyl carrier reductase showed good toxicity properties. The compounds were further evaluated based on the Molecular Dynamics simulation that confirmed the binding stability of the compounds to the targeted proteins. Overall, the lead compounds ZINC38980461, ZINC05378039, and ZINC15772056, were identified for acetyl-coenzyme A (CoA) carboxylase whiles ZINC94085628, ZINC93656835, ZINC94080670, ZINC1774609, ZINC94821232 and ZINC94919772 were identified as lead compounds for enoyl-acyl carrier reductase. The identified compounds can be developed as a treatment option for the malaria disease although, experimental validation is suggested for further evaluation of the work.

show abstract

Section: Discussionmentioning

confidence: 99%

In silico identification of potential inhibitors of acyl carrier protein reductase and acetyl CoA carboxylase of Plasmodium falciparum in antimalarial therapy

Salifu¹,

Abugri²,

Rashid³

et al. 2023

Front. Drug Discov.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Furthermore, molecular dynamic simulations was used to unveil the stability and flexibility of the selected ligands against the two fatty acid targets [48]. The cα atoms of the proteinligand complexes were used to calculate the RMSD of the system that confirm low deviation of the system [48], [49]. Generally, the acceptable threshold for an average change in RMSD of the protein-ligand complex 1-3Å [47].…”

Section: Discussionmentioning

confidence: 99%

Molecular docking studies of potential inhibitors of acyl carrier protein and acetyl CoA Carboxylase in Plasmodium falciparum

Salifu

Rashid

Abugri

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Malaria caused by Plasmodium falciparum, remains one of the most fatal parasitic diseases that has affected nearly a third of the world's population. The major impediment to the treatment of malaria is the emergence of resistance of the P. falciparum parasite to current anti-malaria therapeutics such as Artemisinin (ART)-based combination therapy (ACT). This has resulted in countless efforts to develop novel therapeutics that will counter this resistance with the aim to control and eradicate the disease. The application of in silico modelling techniques has gained a lot of recognition in antimalarial research in recent times through the identification of biological components of the parasite for rational drug design. In this study we employed various in silico techniques such as the Virtual screening, molecular docking and molecular dynamic simulations to identify potential new inhibitors of biotin acetyl-coenzyme A (CoA) carboxylase and enoyl-acyl carrier reductase, two enzyme targets that play a crucial role in fatty acid synthesis in the Plasmodium parasite. Initially, 9 hit compounds were identified for each of the two enzymes from the ZincPharmer database. Subsequently, all hit compounds bind favourably to the active sites of the two enzymes as well as show excellent pharmacokinetic properties. Three (3) of the hits for the biotin acetyl-coenzyme A (CoA) carboxylase and six (6) of the enoyl-acyl carrier reductase showed good toxicity properties. The compounds were further evaluated based on the Molecular Dynamics (MD) simulation that confirmed the binding stability of the compounds to the targeted proteins. Overall, the lead compounds Zinc38980461, Zinc05378039, and Zinc15772056, were identified for acetyl-coenzyme A (CoA) carboxylase whiles zinc94085628, zinc93656835, zinc94080670, zinc1774609, zinc94821232 and Zinc94919772 were identified as lead compounds for enoyl-acyl carrier reductase. The identified compounds can be developed as a treatment option for the malaria disease although, experimental validation is suggested for further evaluation of the work.

show abstract

“…Combined with previous reports, these results suggest that compound mutations of the ALK gene affect the efficacy of first- and second-generation ALK-TKIs. To date, compound mutations of the ALK tyrosine kinase domain have been commonly considered a molecular mechanism of resistance to all-generation ALK-TKIs( Gainor et al, 2016 ; Yoda et al, 2018 ; Okada et al, 2019 ; Takahashi et al, 2020 ; Salifu et al, 2022 ). In only one report, the ALK C1156Y/L1198F composite mutant was found to be resistant to second- and third-generation ALK-TKIs but resensitive to crizotinib ( Shaw et al, 2016a ).…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…The S1189C mutation in the ALK kinase domain has not been reported in previous studies, nor is it recorded in any publicly available databases of oncogenes (such as COSMIC and ClinVar). Although brigatinib (Tu et al, 2019), alectinib (Zhang et al, 2016, and lorlatinib (Syed, 2019), as FDA-approved ALK inhibitors, are effective against the F1174L mutation, previous reports have shown that the ALK gene compound mutation is resistant to almost all ALK-TKI Frontiers in Pharmacology frontiersin.org inhibitors (Gainor et al, 2016;Takahashi et al, 2020;Salifu et al, 2022). ALK compound mutations are mainly seen in the sequential treatment of multiple ALK inhibitors in non-small cell lung cancer patients (Yoda et al, 2018), but the case of de novo F1174L-cis-S1189C mutation as a primary drug-resistant mutation that appeared before targeted therapy has not been reported yet.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Primary resistance to first- and second-generation ALK inhibitors in a non-small cell lung cancer patient with coexisting ALK rearrangement and an ALK F1174L-cis-S1189C de novo mutation: A case report

Zhao

Fan

et al. 2022

Front. Pharmacol.

View full text Add to dashboard Cite

The effectiveness of the tyrosine kinase inhibitor ALK (TKI) for non-small cell lung cancer has been confirmed. However, resistance to ALK-TKIs seems inevitable. Mutations in the ALK kinase domain have been reported as an important mechanism of acquired resistance to ALK therapy. However, patients with de novo ALK kinase domain mutations and ALK rearrangements who were not treated with ALK inhibitors have rarely been reported. Here, we report a case of primary drug resistance to first- and second-generation ALK inhibitors in a NSCLC patient with ALK-rearrangement. The next-generation sequencing test of the pathological biopsy showed that the de novo ALK kinase domain mutation F1174L-cis-S1189C may be the cause of primary drug resistance.

show abstract

Impact of compound mutations I1171N + F1174I and I1171N + L1198H on the structure of ALK in NSCLC pathogenesis: atomistic insights

Cited by 6 publications

References 37 publications

In silico identification of potential inhibitors of acyl carrier protein reductase and acetyl CoA carboxylase of Plasmodium falciparum in antimalarial therapy

In silico identification of potential inhibitors of acyl carrier protein reductase and acetyl CoA carboxylase of Plasmodium falciparum in antimalarial therapy

Molecular docking studies of potential inhibitors of acyl carrier protein and acetyl CoA Carboxylase in Plasmodium falciparum

Primary resistance to first- and second-generation ALK inhibitors in a non-small cell lung cancer patient with coexisting ALK rearrangement and an ALK F1174L-cis-S1189C de novo mutation: A case report

Contact Info

Product

Resources

About