Establishing the mutational effect on the binding susceptibility of AMG510 to KRAS switch II binding pocket: Computational insights

Issahaku, Abdul Rashid; Aljoundi, Aimen; Soliman, Mahmoud E. S.

doi:10.1016/j.imu.2022.100952

Cited by 10 publications

(4 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The energies presented by these compounds suggests the spontaneity, permeation and a measure of the reaction kinetics that characterize their complex formation with the SOS1-KRAS protein. [36] It was also observed that van der Waals, electrostatic and the gas phase terms contribute favourably to the bind of the compounds whiles the solvation term opposed them.…”

Section: Binding Energy Landscape Of Selected Compoundsmentioning

confidence: 98%

Discovery of Potential KRAS‐SOS1 Inhibitors from South African Natural Compounds: An In silico Approach

Issahaku,

Salifu,

Agoni

et al. 2023

ChemistrySelect

Self Cite

View full text Add to dashboard Cite

For decades the direct targeting of KRAS as a driver of non‐small cell lung cancer, colorectal and pancreatic cancers as well as the inhibition of the RAF‐MEK‐ERK pathway has shown little success due to feedback networks that keep the pathway in control. Inhibiting SOS1, a KRAS activator, has therefore become a promising escape route to treating KRAS‐driven cancers. The search for SOS1 inhibitors has since gained momentum although no drug has been approved yet. Owing to the time‐consuming and difficult processes that characterize the discovery and approval of drugs, natural products have become useful in addressing the unmet medical needs. In this study we employed computational techniques to screen South African natural products for inhibitors with the potential to inhibit SOS1‐KRAS activation. In this study, eight natural compounds, from plants and marine life, possessing antineoplastic activities with good docking and ADMET properties were identified. These compounds, viz., SANCDB00219, SANCDB0290, SANCDB00369, SANCDB00416, SANCDB00421, SANCDB00749, SANCDB00957 and SANCDB001124 exhibited favorable total free binding energies in complex with SOS1‐KRAScharacterized by conventional and carbon hydrogen bonds, van der Waals, pi‐alkyl and pi‐sigma interactions with the binding site residues. It was further revealed that these compounds induced conformational stability on the structural architecture of SOS1‐KRAS, and decreased the structural flexibility of its individual C‐α atoms as a mechanism of inhibition. Upon experimental validation, these compounds from a natural origin could serve as lead identification of small molecules to address SOS1‐KRAS associated diseases.

show abstract

Section: Binding Energy Landscape Of Selected Compoundsmentioning

confidence: 98%

Discovery of Potential KRAS‐SOS1 Inhibitors from South African Natural Compounds: An In silico Approach

Issahaku,

Salifu,

Agoni

et al. 2023

ChemistrySelect

Self Cite

View full text Add to dashboard Cite

show abstract

“…With the aim of predicting the binding free energy of the receptor-ligand complex, we used the Molecular Mechanics Poison-Boltzmann Surface Area ( MMPBSA) integrated with the AMBER18 package [28] owing to its extensively reported reliability [34]. The binding energy between the ligand molecule and the receptor protein to form a complex presented in these methods is estimated as follows:…”

Section: Binding a Nity Calculationsmentioning

confidence: 99%

Per-Residue Footprints Guided Pharmacophore Model and Pharmacokinetic Profiles for the Discovery of Potential METTL3 Inhibitors Against Myeloid Leukemia

Mncube,

Issahaku,

Soliman

2024

Preprint

Self Cite

View full text Add to dashboard Cite

The impact of the protein METTL3 on tumorigenesis is well-established in cancer research. It promotes cell growth, invasion, migration, and drug resistance. METTL3 is also involved in the modulation of hematopoietic stem cell differentiation. Inhibiting METTL3 presents a potential therapeutic strategy for myeloid leukemia. This study aimed to identify METTL3 inhibitors through a structure-based virtual screening approach, utilizing an in-house per-residue decomposition virtual screening protocol. We mapped the binding interaction profile of V22, a recognized METTL3 inhibitor, to construct a pharmacophore model for the systematic exploration of potential inhibitors within a chemical database. Four out of nine hit compounds retrieved from ZINC compounds database, showed promising results, and were further investigated. A comprehensive evaluation of the ADMET properties and physicochemical characteristics of these compounds revealed superior qualities compared to V22. Molecular dynamics (MD) trajectory analysis unveiled substantial structural conformational changes induced by these compounds within the METTL3 protein, offering potential insights into therapeutic inhibition. After mapping per-residue interaction footprints and examining toxicity profiles, we successfully identified the critical residues essential for activity and selectivity, informing our inhibitor design. Furthermore, the four compounds exhibited total binding energies of − 45.3 ± 3.3, − 40.1 ± 4.2, − 56.9 ± 3.3, and − 50.1 ± 4.1 kcal/mol for ZINC67367742, ZINC76585975, ZINC76603049, and ZINC76600653, respectively. The structural changes observed in proteins upon binding to specific compounds have important therapeutic implications. These alterations include increased stability, improved structural alignment, reduced flexibility, and greater compactness. These changes make these compounds promising candidates for developing more effective therapeutic inhibitors in the treatment of myeloid leukemia.

show abstract

“…The computed free binding energies shed light on the interactions between compounds and receptors. Due to its proven effectiveness and generally acknowledged dependability, this approach has been frequently used [78–80] . The method is depicted as follows:

\vcenter{\openup.5em\halign{$\displaystyle{#}$\cr \Delta {E}_{bind}={E}_{complex}-({E}_{protein}+{E}_{ligand})\hfill\cr}}

\vcenter{\openup.5em\halign{$\displaystyle{#}$\cr {\Delta G}_{bind}=\ {E}_{MM\ }+\ {G}_{sol}-T\Delta S\hfill\cr}}

…”

Section: Computational Detailsmentioning

confidence: 99%

“…Due to its proven effectiveness and generally acknowledged dependability, this approach has been frequently used. [78][79][80] The method is depicted as follows:…”

Section: Molecular Dynamics Simulationmentioning

confidence: 99%

Leveraging Flavonoids as Potential Inhibitors of METTL3 in Combating Cancer: A Combined Structure‐Based Drug Design and DFT Approach

Abo‐Dya,

Issahaku

2023

ChemistrySelect

Self Cite

View full text Add to dashboard Cite

Methyltransferase‐like 3 (METTL3) serves as a primary catalytic enzyme within the N6‐ methyladenosine (m6 A) methyltransferase system, playing a crucial role in various biological processes. However, its involvement in the pathogenesis of several cancers, have been well documented. The pursuit of small molecule inhibitors to counteract the cancer‐promoting effects of METTL3 has gained considerable momentum; however, no approved drugs are available. In this study, we employed computational techniques, including structure‐based virtual screening, consensus molecular docking, Density Function Theory calculations and MMPBSA energy profiling to identify potential METTL3 inhibitors from flavonoids. ST024026, ST99039 and ST4135876 were identified as promising candidates for METTL3 inhibition, as indicated by their favorable docking scores and robust energy profiles. Notably, their binding interactions were characterized by strong hydrogen bonds and hydrophobic contacts, ensuring high stability within the METTL3 binding site. Furthermore, these compounds exhibited favorable physicochemical properties and ADME characteristics, coupled with minimal toxicity. Notably, their binding induced conformational changes in the protein, underscoring their potential as METLL3 inhibitors. These findings highlight the selected flavonoids as potential novel entry inhibitors subject to modifications and optimizations. To advance this line of research, additional biochemical testing and experimental validation are warranted to facilitate the development of highly selective and effective METTL3 inhibitors.

show abstract

Establishing the mutational effect on the binding susceptibility of AMG510 to KRAS switch II binding pocket: Computational insights

Cited by 10 publications

References 48 publications

Discovery of Potential KRAS‐SOS1 Inhibitors from South African Natural Compounds: An In silico Approach

Discovery of Potential KRAS‐SOS1 Inhibitors from South African Natural Compounds: An In silico Approach

Per-Residue Footprints Guided Pharmacophore Model and Pharmacokinetic Profiles for the Discovery of Potential METTL3 Inhibitors Against Myeloid Leukemia

Leveraging Flavonoids as Potential Inhibitors of METTL3 in Combating Cancer: A Combined Structure‐Based Drug Design and DFT Approach

Contact Info

Product

Resources

About