Mahmoud E. S. Soliman's research while affiliated with University of KwaZulu-Natal and other places

Human plasma kallikrein (PKa) is a member of the serine protease family and serves as a key mediator of the kallikrein-kinin system (KKS), which is known for its regulatory roles in inflammation, vasodilation, blood pressure, and coagulation. Genetic dysregulation of KKS leads to Hereditary Angioedema (HAE), which is characterized by spontaneous, painful swelling in various body regions. Importantly, HAE frequently coexists with various cancers. Despite substantial efforts towards the development of PKa inhibitors for HAE, there remains a need for bifunctional agents addressing both anti-cancer and anti-HAE aspects, especially against carcinoma-associated comorbid HAE conditions. Consequently, we investigated the therapeutic potential of the anti-glutamine prodrug, isopropyl(S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)-propanamido)-6-diazo-5-oxo-hexanoate (DRP-104), and its active form, 6-Diazo-5-oxo-l-norleucine (DON), recognized for their anti-cancer properties, as novel PKa inhibitors. Utilizing structure-based in silico methods, we conducted a comparative analysis with berotralstat, a clinically approved HAE prophylactic, and sebetralstat, an investigational HAE therapeutic agent, in Phase 3 clinical trials. Inhibiting PKa with DON resulted in relatively heightened structural stability, rigidity, restricted protein folding, and solvent-accessible loop exposure, contributing to increased intra-atomic hydrogen bond formation. Conversely, PKa inhibition with DRP-104 induced restricted residue flexibility and significantly disrupted the critical SER195-HIS57 arrangement in the catalytic triad. Both DON and DRP-104, along with the reference drugs, induced strong cooperative intra-residue motion and bidirectional displacement in the PKa architecture. The results revealed favorable binding kinetics of DON/DRP-104, showing thermodynamic profiles that were either superior or comparable to those of the reference drugs. These findings support their consideration for clinical investigations into the management of carcinoma-associated HAE.

Accurate identification of protein binding sites is pivotal for understanding molecular interactions and facilitating drug discovery efforts. However, the dynamic nature of proteinligand interactions presents a formidable challenge, necessitating innovative approaches to bridge the gap between theoretical predictions and experimental realities. This review explores the challenges and recent advancements in protein binding site prediction. Specifically, we highlight the integration of molecular dynamics simulations, machine learning, and deep learning techniques to capture the dynamic and complex nature of protein-ligand interactions. Additionally, we discuss the importance of integrating experimental data, such as structural information and biochemical assays, to enhance prediction accuracy and reliability. By navigating the intersection of classical and the onset of machine learning and deep learning approaches, we aim to provide insights into current state-of-the-art techniques and chart a course for future protein binding site prediction advancements. Ultimately, these efforts could unravel the mysteries of protein-ligand interactions and accelerate drug discovery endeavors.

Cardiovascular disorders are still challenging and are among the deadly diseases. As a major risk factor for atherosclerotic cardiovascular disease, dyslipidemia, and high low‐density lipoprotein cholesterol in particular, can be prevented primary and secondary by lipid‐lowering medications. Therefore, insights are still needed into designing new drugs with minimal side effects. Proprotein convertase subtilisin/kexin 9 (PCSK9) enzyme catalyses protein‐protein interactions with low‐density lipoprotein, making it a critical target for designing promising inhibitors compared to statins. Therefore, we screened for potential compounds using a redesigned PCSK9 conformational behaviour to search for a significantly extensive chemical library and investigated the inhibitory mechanisms of the final compounds using integrated computational methods, from ligand essential functional group screening to all‐atoms MD simulations and MMGBSA‐based binding free energy. The inhibitory mechanisms of the screened compounds compared with the standard inhibitor. K31 and K34 molecules showed stronger interactions for PCSK9, having binding energy (kcal/mol) of −33.39 and −63.51, respectively, against −27.97 of control. The final molecules showed suitable drug‐likeness, non‐mutagenesis, permeability, and high solubility values. The C‐α atoms root mean square deviation and root mean square fluctuation of the bound‐PCSK9 complexes showed stable and lower fluctuations compared to apo PCSK9. The findings present a model that unravels the mechanism by which the final molecules proposedly inhibit the PCSK9 function and could further improve the design of novel drugs against cardiovascular diseases.

Therapeutic activation of G protein-coupled estrogen receptor 1 (GPER-1) shows promise for treating Waldenström's Macroglobulinemia (WM). Recently, the selective small-molecule agonist G-1 or its enantiomer LNS8801 were reported as potent GPER-1 pharmacological activators, however, the molecular events surrounding their chirality towards GPER-1 is still unexplored. This study aimed to explore the molecular events surrounding the chirality of the selective small-molecule agonists G-1 and LNS8801 towards GPER-1. Molecular docking and dynamics simulations revealed strong binding affinities and key amino acid residues involved in the activation process. The results revealed favourable binding affinities of -29.87kcal/mol, and -28.09kcal/mol for G-1 and LNS8801 towards GPER-1, respectively. Per-residue energy decomposition and time-dependent analysis proved that Arg253 and Arg254 are key amino acid residues in binding these activators towards GPER-1. The activators affected stability, flexibility, and structure of GPER-1. G-1 exhibited greater rigidity when bound to GPER-1 compared to LNS880. This study's findings illuminate chirality and the potential for optimizing the enantiomer ratio to enhance inhibitory effects. These results could also reveal the molecular specifics and binding mechanism of the G-1 and its enantiomer LNS8801 with GPER-1, laying the basis for the rational design of enhanced chiral molecules against WM.

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.

Human plasma kallikrein (PKa) is a member of the serine protease family and serves as a key mediator of the kallikrein-kinin system (KKS), which is known for its regulatory roles in inflammation, vasodilation, blood pressure, and coagulation. Genetic dysregulation of KKS leads to Hereditary Angioedema (HAE), which is characterized by spontaneous, painful swelling in various body regions. Importantly, HAE frequently coexists with various cancers. Despite substantial efforts towards the development of PKa inhibitors for HAE, there remains a need for bifunctional agents addressing both anti-cancer and anti-HAE aspects, especially against carcinoma-associated comorbid HAE conditions. Consequently, we investigated the therapeutic potential of the anti-glutamine prodrug, isopropyl(S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)-propanamido)-6-diazo-5-oxo-hexanoate (DRP-104), and its active form, 6-Diazo-5-oxo-l-norleucine (DON), recognized for their anti-cancer properties, as novel PKa inhibitors. Utilizing structure-based in silico methods, we conducted a comparative analysis with berotralstat, a clinically approved HAE prophylactic, and sebetralstat, an investigational HAE therapeutic agent, in Phase 3 clinical trials. Inhibiting PKa with DON resulted in heightened structural stability, rigidity, restricted protein folding, and solvent-accessible loop exposure, contributing to increased intra-atomic hydrogen bond formation. Conversely, PKa inhibition with DRP-104 induced restricted residue flexibility and significantly disrupted the critical SER195-HIS57 arrangement in the catalytic triad. Both DON and DRP-104, along with the reference drugs, induced strong cooperative intra-residue motion and bidirectional displacement in the PKa architecture. The results revealed favorable binding kinetics of DON/DRP-104, showing thermodynamic profiles that were either superior or comparable to those of the reference drugs. These findings support their consideration for clinical investigations into the management of carcinoma-associated HAE.

Triple-negative breast cancer (TNBC) is associated with high-grade invasive carcinoma leading to a 10% to 15% death rate in younger premenopausal women. Targeting cancerous inhibitors of protein phosphatase (CIP2A) has been a highly effective approach for exploring therapeutic drug candidates. Lapatinib, a dual tyrosine kinase inhibitor, has shown promising inhibition properties by inducing apoptosis in TNBC carcinogenesis in vivo. Despite knowledge of the 3D structure of CIP2A, no reports provide insight into CIP2A ligand binding sites. To this effect, we conducted in silico site identification guided by lapatinib binding. Four of the five sites identified were cross-validated, and the stem domain revealed more excellent ligand binding affinity. The binding affinity of lapatinib in these sites was further computed using the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) approach. According to MM/PBSA//200 ns MD simulations, lapatinib exhibited a higher binding affinity against CIP2A in site 2 with ΔG critical values of -37.1 kcal/mol. The steadiness and tightness of lapatinib with CIP2A inside the stem domain disclosed glutamic acid-318 as the culprit amino acid with the highest electrostatic energy. These results provide clear information on the CIP2A domain capable of ligand binding and validate lapatinib as a promising CIP2A inhibitor in TNBC carcinogenesis.

The role of human serum albumin (HSA) in the transport of molecules predicates its involvement in the determination of drug distribution and metabolism. Optimization of ADME properties are analogous to HSA binding thus this is imperative to the drug discovery process. Currently, various in silico predictive tools exist to complement the drug discovery process, however, the prediction of possible ligand-binding sites on HSA has posed several challenges. Herein, we present a strong and deeper-than-surface case for the prediction of HSA-ligand binding sites using multi-cavity molecular descriptors by exploiting all experimentally available and crystallized HSA-bound drugs. Unlike previously proposed models found in literature, we established an in-depth correlation between the physicochemical properties of available crystallized HSA-bound drugs and different HSA binding site characteristics to precisely predict the binding sites of investigational molecules. Molecular descriptors such as the number of hydrogen bond donors (nHD), number of heteroatoms (nHet), topological polar surface area (TPSA), molecular weight (MW), and distribution coefficient (LogD) were correlated against HSA binding site characteristics, including hydrophobicity, hydrophilicity, enclosure, exposure, contact, site volume, and donor/acceptor ratio. Molecular descriptors nHD, TPSA, LogD, nHet, and MW were found to possess the most inherent capacities providing baseline information for the prediction of serum albumin binding site. We believe that these associations may form the bedrock for establishing a solid correlation between the physicochemical properties and Albumin binding site architecture. Information presented in this report would serve as critical in provisions of rational drug designing as well as drug delivery, bioavailability, and pharmacokinetics.

The epidermal growth factor receptor (EGFR) dimerizes upon ligand bindings to the extracellular domain that initiates the downstream signaling cascades and activates intracellular kinase domain. Thus, activation of autophosphorylation through kinase domain results in metastasis, cell proliferation, and angiogenesis. The main objective of this research is to discover more promising anti-cancer lead compound against EGRF from the phenolic acids of marine natural products using in-silico approaches. Phenolic compounds reported from marine sources are reviewed from previous literatures. Furthermore, molecular docking was carried out using the online tool CB-Dock. The molecules with good docking and binding energies scores were subjected to ADME, toxicity and drug-likeness analysis. Subsequently, molecules from the docking experiments were also evaluated using the acute toxicity and MD simulation studies. Fourteen phenolic compounds from the reported literatures were reviewed based on the findings, isolation, characterized and applications. Molecular docking studies proved that the phenolic acids have good binding fitting by forming hydrogen bonds with amino acid residues at the binding site of EGFR. Chlorogenic acid, Chicoric acid and Rosmarinic acid showed the best binding energies score and forming hydrogen bonds with amino acid residues compare to the reference drug Erlotinib. Among these compounds, Rosmarinic acid showed the good pharmacokinetics profiles as well as acute toxicity profile. The MD simulation study further revealed that the lead complex is stable and could be future drug to treat the cancer disease. Furthermore, in a wet lab environment, both in-vitro and in-vivo testing will be employed to validate the existing computational results.

Targeting C-X-C motif chemokine receptor 4 (CXCR4), as an oncogenic factor in Waldenström’s Macroglobulinemia (WM), has been considered a promising treatment strategy, and various CXCR4 antagonists, such as small molecules, peptides, and antibodies, are currently in preclinical and clinical phases. Recently, a 16-mer fragment of human serum albumin, the most abundant protein in plasma, has been identified as a potent inhibitor of CXCR4. Hence, it was given the name Endogenous Peptide Inhibitor of CXCR4 (EPI-X4) and demonstrated a less toxic alternative to the current therapies due to its improved selectivity profile. Further research has led to the discovery of optimized EPI-X4 derivatives, JM#21, and WSC02, as potent CXCR4 antagonists. Despite the ongoing research in this area, the molecular basis of how EPI-X4 and its derivatives bind to CXCR4 is still unexplored. In this study, three aspects were investigated using molecular dynamics (MD) simulations and binding energy calculations: (1) mapping the structure- function of the amino acid sequence composition of the peptides to determine the contribution of each amino acid towards the overall binding to CXCR4, as well as the key interaction peptide motifs; (2) the detailed binding mechanism of EPI-X4, JM#21, and WSC02 against CXCR4 at the molecular level; and (3) the impact of peptide binding on the conformational landscape of CXCR4. Per-residue energy decomposition analysis revealed that the inclusion of arginine residue in the peptide sequence has significantly improved the binding affinity towards CXCR4, particularly at positions Arg3 for EPI-X4 and WSC02 and Arg3 and Arg6 for JM#21. This may explain the finding that JM#21 exhibited the highest binding affinity. Additionally, MD simulations coupled with thermodynamic calculations provided a comprehensive picture of the “dynamic” interaction motif of the peptides with CXCR4. Separate MD simulations in a POPC bilayer were executed to determine its effect on the binding energy. This study provides molecular insights into the binding mechanism of the endogenous peptide EPI-X4 and its optimized derivatives with CXCR4, laying the basis for the rational design of optimized peptide derivatives against WM.