Biology subjects

Ikram, S.

Publications and source records attributed to Ikram, S..

4 recordsLinked to original sources

bioRxiv2024

Employing Steered MD Simulations for Effective Virtual Screening: Active Pharmacophore Search by Dynamic Corrections to target MKK3-MYC Interactions

The intricate relationship between mitogen-activated protein kinase 3 (MKK3) and MYC proto-oncogene protein (MYC) activation holds deep implications for the progression of cancer, particularly in the context of triple negative breast cancer (TNBC). Despite significant progress, the challenge of discovering effective MYC-targeted drugs persists, demanding innovative approaches to control MYC-dependent malignancies. A promising avenue in this pursuit involves disrupting the protein-protein interactions (PPIs) between MKK3 and MYC. The significance of this interaction is emphasized by the activation of MYC by MKK3 in diverse cell types, presenting a novel perspective for therapeutic interventions in MYC-driven pathways. In the current study, a novel in silico strategy to screen small molecule libraries that target the MKK3-MYC interaction was conducted. Dynamic structure-based pharmacophore models were developed and utilized for screening the small molecule libraries, enabling the identification of compounds exhibiting favorable alignment with the defined pharmacophore features. Subsequently, physics-based simulations approaches were conducted on these selected hit molecules. Steered molecular dynamics (sMD) simulations were utilized to assess the correlation between the necessary forces to dissociate candidate hit ligands from the binding pocket and their corresponding average binding free energies (MM/GBSA). Comparative analysis of the average binding free energies of the identified hits obtained from the small molecule libraries represent that the identified compounds have promising predicted binding affinities compared to the reference molecule SGI-1027. Therefore, these findings may signify a crucial advancement in our ability to control MYC activation in cancer.

bioinformatics↗

bioRxiv2020

Impact of the radiated brain microenvironment on a panel of human patient-derived xenografts.

ObjectiveRadiotherapy, combined with surgical resection and chemotherapy, remains a first-line treatment for infiltrative gliomas. However, these tumor are not surgically curable, and often recur, even within the prior radiation field, and may demonstrate a more aggressive phenotype. We recently demonstrated that the radiated brain tumor microenvironment promotes tumor aggressiveness in an orthotopic patient-derived xenograft (PDX) model of glioblastoma (Mayo GBM 143). Importantly, high grade gliomas display diverse molecular phenotypes, and whether this genetic variability leads to divergent behaviour in the radiated tumor microenvironment is unknown. Herein, we characterize the effects of the irradiated brain microenvinroment on nine additional unique GBM cell lines to better understand the nuances of how tumor molecular phenotypes influence cellular dynamics. MethodsFemale athymic nude mice were randomly divided into cranial radiation (15 Gy) and non-radiated groups. Mice then underwent intracranial implantation with one of the selected PDX GBM cell lines (GBM 6, 10, 12, 39, 46, 76, 123, 164, 196; total n=8-15, per group, per line). GBM 6 cells were additionally implanted 6 months after completion of fractionated radiation (4Gy x 10 fractions or 2Gy x 30 fractions) vs sham radiation. Kaplan-Meyer (K-M) and log-rank tests were performed to compare the survival between irradiated and non-irradiated groups. ResultOf nine previously untested human GBM lines, we found that five demonstrated shorter survival in the pre-radiated brain (GBM 6, 46, 76, 164, 196); similar to previous observations with GBM 143. GBM 6 was also evaluated 6 months after fractionated radiation yielding similar results. However, two lines yielded prolonged survival in the pre-radiated brain (GBM 10, 12); GBM12 and 10 demonstrated the fastest baseline growth in the non-radiated brain; GBM 39, 123 whose rate of growth was not impacted by the radiated brain, demonstrated a an intermediate baseline growth rate between that of those positively and negatively impacted by the radiated brain microenvironment. No other clinical or molecular phenotype was found to consistently correlate with response to the radiated microenvironment. ConclusionAmong a total of 10 total human GBM lines evaluated to date, 60% induce faster mortality in a radiated microenvironment, and 20% induce slower mortality. These results highlight the likely critical impact of the irradiated microenvironment on tumor behaviour, yet illustrate that different tumors may exhibit opposing responses. Although further evaluation will be needed to understand mechanisms of divergent behavior, our data suggest the increased rate of growth in the radiated microenvironment may not apply to the fastest-growing tumor lines, which could instead demonstrate a paradoxical response.

cancer biology↗

bioRxiv2019

Mitogenomic Diversity in Sacred Ibis Mummies sheds light on early Egyptian practices

The ancient catacombs of Egypt harbor millions of well-preserved mummified Sacred Ibis (Threskiornis aethiopicus) dating from [~]600BC. Although it is known that a very large number of these votive mummies were sacrificed to the Egyptian God Thoth, how the ancient Egyptians obtained millions of these birds for mummification remains unresolved. Ancient Egyptian textual evidences suggest they may have been raised in dedicated large-scale farms. To investigate the most likely method used by the priests to secure birds for mummification, we report the first study of complete mitochondrial genomes of 14 Sacred Ibis mummies interred [~]2500 years ago. We analysed and compared the mitogenomic diversity among Sacred Ibis mummies to that found in modern Sacred Ibis populations from throughout Africa. The ancient birds show a high level of genetic variation comparable to that identified in modern African populations, contrary to the suggestion in ancient hieroglyphics (or ancient writings) of centralized industrial scale farming of sacrificial birds. This suggests a sustained short-term taming of the wild Sacred Ibis for the ritual yearly demand.

evolutionary biology↗

bioRxiv2018

Fishing for Mitochondrial DNA in The Egyptian Sacred Ibis Mummies

The long-term preservation of DNA requires a number of optimal conditions, including consistent exposure to cool, dry, and dark environments. As a result, the successful recovery of ancient DNA from material from warmer climates such as those in Egypt has often been met with scepticism. Egypt has an abundance of ancient mummified animals and humans, whose genetic analyses would offer important insights into ancient cultural practices. To date, the retrieval of complete genomes from ancient Egyptian remains of humans or other animals has been largely unsuccessful. To test for the presence of even short DNA sequences in Egyptian material, we performed second-generation shotgun sequencing of DNA libraries constructed from ancient Sacred Ibis mummies. Since most of the resulting Illumina libraries were shown to contain extremely low levels (less than 0.06%) of endogenous mitochondrial DNA, we aimed to enrich these samples using targeted in-solution hybridisation methods. Using biotinylated RNA baits designed to Sacred Ibis complete mitochondrial sequences, we trialled a number of conditions and parameters and achieved up to 4705-fold enrichment. We also found that a combination of hybridisation temperature and the use of the polymerase KAPA HiFi significantly increased both the efficiency of targeted hybridisation and post-hybridisation amplification respectively. Furthermore, improved enrichment was accompanied with only minor increases in clonality. Our method enabled us to reconstruct the first complete mitochondrial genomes from ancient Egyptian sub-fossil material.

genomics↗