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Deciphering Mutational Impacts on c-Src-HK2 Interaction in Colorectal Cancer Progression, and Identification of Potential Phytocompounds Inhibitors: A Molecular Simulation and Free Energy Calculation Approach

Suleman M, Faizullah, Khan A, Mohammad Sayaf A, Alghamdi A, Alghamdi SA, et al.

Curr Med Chem, 2024 Aug 27.
PMID: 39253929 DOI: 10.2174/0109298673311962240815055821

BACKGROUND: Colorectal cancer (CRC) stands as the third most widespread cancer worldwide in both men and women, witnessing a concerning rise, especially in younger demographics. Abnormal activation of the Non-Receptor Tyrosine Kinase c-Src has been linked to the advancement of several human cancers, including colorectal, breast, lung, and pancreatic ones. The interaction between c-Src and Hexokinase 2 (HK2) triggers enzyme phosphorylation, significantly boosting glycolysis, and ultimately contributing to the development of CRC.
OBJECTIVES: The objectives of this study are to examine the influence of newly identified mutations on the interaction between c-Src and the HK2 enzyme and to discover potent phytocompounds capable of disrupting this interaction.
METHODS: In this study, we utilized molecular docking to check the effect of the identified mutation on the binding of c-Src with HK2. Virtual drug screening, MD simulation, and binding free energy were employed to identify potent drugs against the binding interface of c-Src and HK2.
RESULTS: Among these mutations, six (W151C, L272P, A296S, A330D, R391H, and P434A) were observed to significantly disrupt the stability of the c-Src structure. Additionally, through molecular docking analysis, we demonstrated that the mutant forms of c-Src exhibited high binding affinities with HK2. The wildtype showed a docking score of -271.80 kcal/mol, while the mutants displayed scores of -280.77 kcal/mol, -369.01 kcal/mol, -324.41 kcal/mol, -362.18 kcal/mol, 266.77 kcal/mol, and -243.28 kcal/mol for W151C, L272P, A296S, A330D, R391H, and P434A respectively. Furthermore, we identified five lead phytocompounds showing strong potential to impede the binding of c-Src with HK2 enzyme, essential for colon cancer progression. These compounds exhibit robust bonding with c-Src with docking scores of -7.37 kcal/mol, -7.26 kcal/mol, -6.88 kcal/mol, -6.81 kcal/mol, and -6.73 kcal/mol. Moreover, these compounds demonstrate dynamic stability, structural compactness, and the lowest residual fluctuation during MD simulation. The binding free energies for the top five hits (-42.44±0.28 kcal/mol, -28.31±0.25 kcal/mol, -34.95±0.44 kcal/mol, -38.92±0.25 kcal/mol, and -30.34±0.27 kcal/mol), further affirm the strong interaction of these drugs with c-Src which might impede the cascade of events that drive the progression of colon cancer.
CONCLUSION: Our findings serve as a promising foundation, paving the way for future discoveries in the fight against colorectal cancer.
Genome-wide screening of vaccine targets prioritization and reverse vaccinology aided design of peptides vaccine to enforce humoral immune response against Campylobacter jejuni

Zeb A, Ali SS, Azad AK, Safdar M, Anwar Z, Suleman M, et al.

Comput Biol Med, 2021 06;133:104412.
PMID: 33934066 DOI: 10.1016/j.compbiomed.2021.104412

Campylobacter jejuni, gram-negative bacteria, is an infectious agent of foodborne disease-causing bloody diarrhea, abdominal pain, fever, Guillain-Barré syndrome (GBS) and Miller Fisher syndrome in humans. Campylobacter spp. with multidrug resistance to fluoroquinolones, tetracycline, and erythromycin are reported. Hence, an effective vaccine candidate would provide long-term immunity against C. jejuni infections. Thus, we used a subtractive proteomics pipeline to prioritize essential proteins, which impart a critical role in virulence, replication and survival. Five proteins, i.e. Single-stranded DNA-binding protein, UPF0324 membrane protein Cj0999c, DNA translocase FtsK, 50S ribosomal protein L22, and 50S ribosomal protein L1 were identified as virulent proteins and selected for vaccine designing. We reported that the multi-epitopes subunit vaccine based on CTL, HTL and B-cell epitopes combination possess strong antigenic properties and associates no allergenic reaction. Further investigation revealed that the vaccine interacts with the immune receptor (TLR-4) and triggered the release of primary and secondary immune factors. Moreover, the CAI and GC contents obtained through codon optimization were reported to be 0.93 and 53% that confirmed a high expression in the selected vector. The vaccine designed in this study needs further scientific consensus and will aid in managing C. jejuni infections.
Fulltext Pharmacotherapeutic Potential of Natural Products to Target the SARS-CoV-2 PLpro Using Molecular Screening and Simulation Approaches

Sayaf AM, Ahmad H, Aslam MA, Ghani SA, Bano S, Yousafi Q, et al.

Appl Biochem Biotechnol, 2023 Nov;195(11):6959-6978.
PMID: 36961512 DOI: 10.1007/s12010-023-04466-1

Because of the essential role of PLpro in the regulation of replication and dysregulation of the host immune sensing, it is considered a therapeutic target for novel drug development. To reduce the risk of immune evasion and vaccine effectiveness, small molecular therapeutics are the best complementary approach. Hence, we used a structure-based drug-designing approach to identify potential small molecular inhibitors for PLpro of SARS-CoV-2. Initial scoring and re-scoring of the best hits revealed that three compounds NPC320891 (2,2-Dihydroxyindene-1,3-Dione), NPC474594 (Isonarciclasine), and NPC474595 (7-Deoxyisonarciclasine) exhibit higher docking scores than the control GRL0617. Investigation of the binding modes revealed that alongside the essential contacts, i.e., Asp164, Glu167, Tyr264, and Gln269, these molecules also target Lys157 and Tyr268 residues in the active site. Moreover, molecular simulation demonstrated that the reported top hits also possess stable dynamics and structural packing. Furthermore, the residues' flexibility revealed that all the complexes demonstrated higher flexibility in the regions 120-140, 160-180, and 205-215. The 120-140 and 160-180 lie in the finger region of PLpro, which may open/close during the simulation to cover the active site and push the ligand inside. In addition, the total binding free energy was reported to be - 32.65 ± 0.17 kcal/mol for the GRL0617-PLpro, for the NPC320891-PLpro complex, the TBE was - 35.58 ± 0.14 kcal/mol, for the NPC474594-PLpro, the TBE was - 43.72 ± 0.22 kcal/mol, while for NPC474595-PLpro complex, the TBE was calculated to be - 41.61 ± 0.20 kcal/mol, respectively. Clustering of the protein's motion and FEL further revealed that in NPC474594 and NPC474595 complexes, the drug was seen to have moved inside the binding cavity along with the loop in the palm region harboring the catalytic triad, thus justifying the higher binding of these two molecules particularly. In conclusion, the overall results reflect favorable binding of the identified hits strongly than the control drug, thus demanding in vitro and in vivo validation for clinical purposes.
Fulltext Exploring the natural products chemical space to abrogate the F3L-dsRNA interface of monkeypox virus to enhance the immune responses using molecular screening and free energy calculations

Suleman M, Ahmad T, Shah K, Albekairi NA, Alshammari A, Khan A, et al.

Front Pharmacol, 2023;14:1328308.
PMID: 38269277 DOI: 10.3389/fphar.2023.1328308

Amid the ongoing monkeypox outbreak, there is an urgent need for the rapid development of effective therapeutic interventions capable of countering the immune evasion mechanisms employed by the monkeypox virus (MPXV). The evasion strategy involves the binding of the F3L protein to dsRNA, resulting in diminished interferon (IFN) production. Consequently, our current research focuses on utilizing virtual drug screening techniques to target the RNA binding domain of the F3L protein. Out of the 954 compounds within the South African natural compound database, only four demonstrated notable docking scores: -6.55, -6.47, -6.37, and -6.35 kcal/mol. The dissociation constant (KD) analysis revealed a stronger binding affinity of the top hits 1-4 (-5.34, -5.32, -5.29, and -5.36 kcal/mol) with the F3L in the MPXV. All-atom simulations of the top-ranked hits 1 to 4 consistently exhibited stable dynamics, suggesting their potential to interact effectively with interface residues. This was further substantiated through analyses of parameters such as radius of gyration (Rg), Root Mean Square Fluctuation, and hydrogen bonding. Cumulative assessments of binding free energy confirmed the top-performing candidates among all the compounds, with values of -35.90, -52.74, -28.17, and -32.11 kcal/mol for top hits 1-4, respectively. These results indicate that compounds top hit 1-4 could hold significant promise for advancing innovative drug therapies, suggesting their suitability for both in vivo and in vitro experiments.
Structural vaccinology, molecular simulation and immune simulation approaches to design multi-epitopes vaccine against John Cunningham virus

Suleman M, Khan TA, Ejaz H, Maroof S, Alshammari A, Albekairi NA, et al.

Microb Pathog, 2024 Apr;189:106572.
PMID: 38354987 DOI: 10.1016/j.micpath.2024.106572

The JCV (John Cunningham Virus) is known to cause progressive multifocal leukoencephalopathy, a condition that results in the formation of tumors. Symptoms of this condition such as sensory defects, cognitive dysfunction, muscle weakness, homonosapobia, difficulties with coordination, and aphasia. To date, there is no specific and effective treatment to completely cure or prevent John Cunningham polyomavirus infections. Since the best way to control the disease is vaccination. In this study, the immunoinformatic tools were used to predict the high immunogenic and non-allergenic B cells, helper T cells (HTL), and cytotoxic T cells (CTL) epitopes from capsid, major capsid, and T antigen proteins of JC virus to design the highly efficient subunit vaccines. The specific immunogenic linkers were used to link together the predicted epitopes and subjected to 3D modeling by using the Robetta server. MD simulation was used to confirm that the newly constructed vaccines are stable and properly fold. Additionally, the molecular docking approach revealed that the vaccines have a strong binding affinity with human TLR-7. The codon adaptation index (CAI) and GC content values verified that the constructed vaccines would be highly expressed in E. coli pET28a (+) plasmid. The immune simulation analysis indicated that the human immune system would have a strong response to the vaccines, with a high titer of IgM and IgG antibodies being produced. In conclusion, this study will provide a pre-clinical concept to construct an effective, highly antigenic, non-allergenic, and thermostable vaccine to combat the infection of the John Cunningham virus.
Abrogation of ORF8-IRF3 binding interface with Carbon nanotube derivatives to rescue the host immune system against SARS-CoV-2 by using molecular screening and simulation approaches

Suleman M, Murshed A, Imran K, Khan A, Ali Z, Albekairi NA, et al.

BMC Chem, 2024 May 11;18(1):99.
PMID: 38734638 DOI: 10.1186/s13065-024-01185-4

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has led to over six million deaths worldwide. In human immune system, the type 1 interferon (IFN) pathway plays a crucial role in fighting viral infections. However, the ORF8 protein of the virus evade the immune system by interacting with IRF3, hindering its nuclear translocation and consequently downregulate the type I IFN signaling pathway. To block the binding of ORF8-IRF3 and inhibit viral pathogenesis a quick discovery of an inhibitor molecule is needed. Therefore, in the present study, the interface between the ORF8 and IRF3 was targeted on a high-affinity carbon nanotube by using computational tools. After analysis of 62 carbon nanotubes by multiple docking with the induced fit model, the top five compounds with high docking scores of - 7.94 kcal/mol, - 7.92 kcal/mol, - 7.28 kcal/mol, - 7.19 kcal/mol and - 7.09 kcal/mol (top hit1-5) were found to have inhibitory activity against the ORF8-IRF3 complex. Molecular dynamics analysis of the complexes revealed the high compactness of residues, stable binding, and strong hydrogen binding network among the ORF8-nanotubes complexes. Moreover, the total binding free energy for top hit1-5 was calculated to be - 43.21 ± 0.90 kcal/mol, - 41.17 ± 0.99 kcal/mol, - 48.85 ± 0.62 kcal/mol, - 43.49 ± 0.77 kcal/mol, and - 31.18 ± 0.78 kcal/mol respectively. These results strongly suggest that the identified top five nanotubes (hit1-5) possess significant potential for advancing and exploring innovative drug therapies. This underscores their suitability for subsequent in vivo and in vitro experiments, marking them as promising candidates worthy of further investigation.
Fulltext Molecular screening of phytocompounds targeting the interface between influenza A NS1 and TRIM25 to enhance host immune responses

Suleman M, Sayaf AM, Khan A, Khan SA, Albekairi NA, Alshammari A, et al.

J Infect Public Health, 2024 Jul;17(7):102448.
PMID: 38815532 DOI: 10.1016/j.jiph.2024.05.005

BACKGROUND: Influenza A virus causes severe respiratory illnesses, especially in developing nations where most child deaths under 5 occur due to lower respiratory tract infections. The RIG-I protein acts as a sensor for viral dsRNA, triggering interferon production through K63-linked poly-ubiquitin chains synthesized by TRIM25. However, the influenza A virus's NS1 protein hinders this process by binding to TRIM25, disrupting its association with RIG-I and preventing downstream interferon signalling, contributing to the virus's evasion of the immune response.
METHODS: In our study we used structural-based drug designing, molecular simulation, and binding free energy approaches to identify the potent phytocompounds from various natural product databases (>100,000 compounds) able to inhibit the binding of NS1 with the TRIM25.
RESULTS: The molecular screening identified EA-8411902 and EA-19951545 from East African Natural Products Database, NA-390261 and NA-71 from North African Natural Products Database, SA-65230 and SA- 4477104 from South African Natural Compounds Database, NEA- 361 and NEA- 4524784 from North-East African Natural Products Database, TCM-4444713 and TCM-6056 from Traditional Chinese Medicines Database as top hits. The molecular docking and binding free energies results revealed that these compounds have high affinity with the specific active site residues (Leu95, Ser99, and Tyr89) involved in the interaction with TRIM25. Additionally, analysis of structural dynamics, binding free energy, and dissociation constants demonstrates a notably stronger binding affinity of these compounds with the NS1 protein. Moreover, all selected compounds exhibit exceptional ADMET properties, including high water solubility, gastrointestinal absorption, and an absence of hepatotoxicity, while adhering to Lipinski's rule.
CONCLUSION: Our molecular simulation findings highlight that the identified compounds demonstrate high affinity for specific active site residues involved in the NS1-TRIM25 interaction, exhibit exceptional ADMET properties, and adhere to drug-likeness criteria, thus presenting promising candidates for further development as antiviral agents against influenza A virus infections.
Molecular exploration of natural and synthetic compounds databases for promising hypoxia inducible factor (HIF) Prolyl-4- hydroxylase domain (PHD) inhibitors using molecular simulation and free energy calculations

Sayaf AM, Kousar K, Suleman M, Albekairi NA, Alshammari A, Mohammad A, et al.

BMC Chem, 2024 Nov 26;18(1):236.
PMID: 39593151 DOI: 10.1186/s13065-024-01347-4

Hypoxia-inducible factors (HIFs) are transcription factors that regulate erythropoietin (EPO) synthesis and red blood cell (RBC) production. Prolyl-4-hydroxylase domain (PHD) enzymes are key regulators of HIF's stability and activity. Inhibiting PHD enzymes can enhance HIF-mediated responses and have therapeutic potential for diseases such as anemia, cancer, stroke, ischemia, neurodegeneration, and inflammation. In this study, we searched for novel PHD inhibitors from four databases of natural products and synthetic compounds: AfroDb Natural Products, AnalytiCon Discovery Natural Product (NP), HIM-Herbal Ingredients In-Vivo Metabolism, and Herbal Ingredients' Targets, with a total number of 13,597 compounds. We screened the candidate compounds by molecular docking and validated them by molecular dynamics simulations and free energy calculations. We identified four target hits (ZINC36378940, ZINC2005305, ZINC31164438, and ZINC67910437) that showed stronger binding affinity to PHD2 compared to the positive control, Vadadustat (AKB-6548), with docking scores of - 13.34 kcal/mol, - 12.76 kcal/mol, - 11.96 kcal/mol, - 11.41 kcal/mol, and - 9.04 kcal/mol, respectively. The target ligands chelated the active site iron and interacted with key residues (Arg 383, Tyr329, Tyr303) of PHD2, in a similar manner as Vadadustat. Moreover, the dynamic stability-based assessment revealed that they also exhibited stable dynamics and compact trajectories. Then the total binding free energy was calculated for each complex which revealed that the control has a TBE of - 31.26 ± 0.30 kcal/mol, ZINC36378940 reported a TBE of - 38.65 ± 0.51 kcal/mol, for the ZINC31164438 the TBE was - 26.16 ± 0.30 kcal/mol while the ZINC2005305 complex reported electrostatic energy of - 32.75 ± 0.58 kcal/mol. This shows that ZINC36378940 is the best hit than the other and therefore further investigation should be performed for the clinical usage. Our results suggest that these target hits are promising candidates that reserve further in vitro and in vivo validations as potential PHD inhibitors for the treatment of renal anemia, cancer, stroke, ischemia, neurodegeneration, and inflammation.
Fulltext Blocking key mutated hotspot residues in the RBD of the omicron variant (B.1.1.529) with medicinal compounds to disrupt the RBD-hACE2 complex using molecular screening and simulation approaches

Khan A, Randhawa AW, Balouch AR, Mukhtar N, Sayaf AM, Suleman M, et al.

RSC Adv, 2022 Mar 01;12(12):7318-7327.
PMID: 35424688 DOI: 10.1039/d2ra00277a

A new variant of SARS-CoV-2 known as the omicron variant (B.1.1.529) reported in South Africa with 30 mutations in the whole spike protein, among which 15 mutations are in the receptor-binding domain, is continuously spreading exponentially around the world. The omicron variant is reported to be highly contagious with antibody-escaping activity. The emergence of antibody-escaping variants is alarming, and thus the quick discovery of small molecule inhibitors is needed. Hence, the current study uses computational drug screening and molecular dynamics simulation approaches (replicated) to identify novel drugs that can inhibit the binding of the receptor-binding domain (RBD) with hACE2. Screening of the North African, East African and North-East African medicinal compound databases by employing a multi-step screening approach revealed four compounds, namely (-)-pipoxide (C1), 2-(p-hydroxybenzyl) benzofuran-6-ol (C2), 1-(4-hydroxy-3-methoxyphenyl)-2-{4-[(E)-3-hydroxy-1-propenyl]-2-methoxyphenoxy}-1,3-propanediol (C3), and Rhein (C4), with excellent anti-viral properties against the RBD of the omicron variant. Investigation of the dynamics demonstrates stable behavior, good residue flexibility profiles, and structural compactness. Validation of the top hits using computational bioactivity analysis, binding free energy calculations and dissociation constant (K D) analysis also indicated the anti-viral properties of these compounds. In conclusion, this study will help in the design and discovery of novel drug therapeutics, which may be used against the emerging omicron variant of SARS-CoV-2.
Fulltext Computational modelling of potentially emerging SARS-CoV-2 spike protein RBDs mutations with higher binding affinity towards ACE2: A structural modelling study

Khan A, Hussain S, Ahmad S, Suleman M, Bukhari I, Khan T, et al.

Comput Biol Med, 2022 Feb;141:105163.
PMID: 34979405 DOI: 10.1016/j.compbiomed.2021.105163

The spike protein of SARS-CoV-2 and the host ACE2 receptor plays a vital role in the entry to the cell. Among which the hotspot residue 501 is continuously subjected to positive selection pressure and induces unusual virulence. Keeping in view the importance of the hot spot residue 501, we predicted the potentially emerging structural variants of 501 residue. We analyzed the binding pattern of wild type and mutants (Spike RBD) to the ACE2 receptor by deciphering variations in the amino acids' interaction networks by graph kernels along with evolutionary, network metrics, and energetic information. Our analysis revealed that N501I, N501T, and N501V increase the binding affinity and alter the intra and inter-residue bonding networks. The N501T has shown strong positive selection and fitness in other animals. Docking results and repeated simulations (three times) confirmed the structural stability and tighter binding of these three variants, correlated with the previous results following the global stability trend. Consequently, we reported three variants N501I, N501T, and N501V could worsen the situation further if they emerged. The relations between the viral fitness and binding affinity is a complicated game thus the emergence of high affinity mutations in the SARS-CoV-2 RBD brings up the question of whether or not positive selection favours these mutations or not?
Fulltext The Global, Regional, and National Burden of Adult Lip, Oral, and Pharyngeal Cancer in 204 Countries and Territories: A Systematic Analysis for the Global Burden of Disease Study 2019

GBD 2019 Lip, Oral, and Pharyngeal Cancer Collaborators, Cunha ARD, Compton K, Xu R, Mishra R, Drangsholt MT, et al.

JAMA Oncol, 2023 Oct 01;9(10):1401-1416.
PMID: 37676656 DOI: 10.1001/jamaoncol.2023.2960

IMPORTANCE: Lip, oral, and pharyngeal cancers are important contributors to cancer burden worldwide, and a comprehensive evaluation of their burden globally, regionally, and nationally is crucial for effective policy planning.
OBJECTIVE: To analyze the total and risk-attributable burden of lip and oral cavity cancer (LOC) and other pharyngeal cancer (OPC) for 204 countries and territories and by Socio-demographic Index (SDI) using 2019 Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study estimates.
EVIDENCE REVIEW: The incidence, mortality, and disability-adjusted life years (DALYs) due to LOC and OPC from 1990 to 2019 were estimated using GBD 2019 methods. The GBD 2019 comparative risk assessment framework was used to estimate the proportion of deaths and DALYs for LOC and OPC attributable to smoking, tobacco, and alcohol consumption in 2019.
FINDINGS: In 2019, 370 000 (95% uncertainty interval [UI], 338 000-401 000) cases and 199 000 (95% UI, 181 000-217 000) deaths for LOC and 167 000 (95% UI, 153 000-180 000) cases and 114 000 (95% UI, 103 000-126 000) deaths for OPC were estimated to occur globally, contributing 5.5 million (95% UI, 5.0-6.0 million) and 3.2 million (95% UI, 2.9-3.6 million) DALYs, respectively. From 1990 to 2019, low-middle and low SDI regions consistently showed the highest age-standardized mortality rates due to LOC and OPC, while the high SDI strata exhibited age-standardized incidence rates decreasing for LOC and increasing for OPC. Globally in 2019, smoking had the greatest contribution to risk-attributable OPC deaths for both sexes (55.8% [95% UI, 49.2%-62.0%] of all OPC deaths in male individuals and 17.4% [95% UI, 13.8%-21.2%] of all OPC deaths in female individuals). Smoking and alcohol both contributed to substantial LOC deaths globally among male individuals (42.3% [95% UI, 35.2%-48.6%] and 40.2% [95% UI, 33.3%-46.8%] of all risk-attributable cancer deaths, respectively), while chewing tobacco contributed to the greatest attributable LOC deaths among female individuals (27.6% [95% UI, 21.5%-33.8%]), driven by high risk-attributable burden in South and Southeast Asia.
CONCLUSIONS AND RELEVANCE: In this systematic analysis, disparities in LOC and OPC burden existed across the SDI spectrum, and a considerable percentage of burden was attributable to tobacco and alcohol use. These estimates can contribute to an understanding of the distribution and disparities in LOC and OPC burden globally and support cancer control planning efforts.

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