Ndumiso N. Mhlongo

Metal complexes in cancer therapy – an update from drug design perspective

In the past, metal-based compounds were widely used in the treatment of disease conditions, but the lack of clear distinction between the therapeutic and toxic doses was a major challenge. With the discovery of cisplatin by Barnett Rosenberg in 1960, a milestone in the history of metal-based compounds used in the treatment of cancers was witnessed. This forms the foundation for the modern era of the metal-based anticancer drugs. Platinum drugs, such as cisplatin, carboplatin and oxaliplatin, are the mainstay of the metal-based compounds in the treatment of cancer, but the delay in the therapeutic accomplishment of other metal-based compounds hampered the progress of research in this field. Recently, however, there has been an upsurge of activities relying on the structural information, aimed at improving and developing other forms of metal-based compounds and nonclassical platinum complexes whose mechanism of action is distinct from known drugs such as cisplatin. In line with this, many more metal-based compounds have been synthesized by redesigning the existing chemical structure through ligand substitution or building the entire new compound with enhanced safety and cytotoxic profile. However, because of increased emphasis on the clinical relevance of metal-based complexes, a few of these drugs are currently on clinical trial and many more are awaiting ethical approval to join the trial. In this review, we seek to give an overview of previous reviews on the cytotoxic effect of metal-based complexes while focusing more on newly designed metal-based complexes and their cytotoxic effect on the cancer cell lines, as well as on new approach to metal-based drug design and molecular target in cancer therapy. We are optimistic that the concept of selective targeting remains the hope of the future in developing therapeutics that would selectively target cancer cells and leave healthy cells unharmed.

A critical survey of average distances between catalytic carboxyl groups in glycoside hydrolases

Published X‐ray crystallographic structures for glycoside hydrolases (GHs) from 39 different families are surveyed according to some rigorous selection criteria, and the distances separating 208 pairs of catalytic carboxyl groups (20 α‐retaining, 87 β‐retaining, 38 α‐inverting, and 63 β‐inverting) are analyzed. First, the average of all four inter‐carboxyl O…O distances for each pair is determined; second, the mean of all the pair‐averages within each GH family is determined; third, means are determined for groups of GH families. No significant differences are found for free structures compared with those complexed with a ligand in the active site of the enzyme, nor for α‐GHs as compared with β‐GHs. The mean and standard deviation (1σ) of the unimodal distribution of average O…O distances for all families of inverting GHs is 8 ± 2Å, with a very wide range from 5Å (GH82) to nearly 13Å (GH46). The distribution of average O…O distances for all families of retaining GHs appears to be bimodal: the means and standard deviations of the two groups are 4.8 ± 0.3Å and 6.4 ± 0.6Å. These average values are more representative, and more likely to be meaningful, than the often‐quoted literature values, which are based on a very small sample of structures. The newly‐updated average values proposed here may alter perceptions about what separations between catalytic residues are “normal” or “abnormal” for GHs. Proteins 2014; 82:1747–1755.

Sliding Clamp of DNA Polymerase III as a Drug Target for TB Therapy: Comprehensive Conformational and Binding Analysis from Molecular Dynamic Simulations

Tuberculosis, caused by Mycobacterium tuberculosis, is one of the most common causes of death in the world. Mycobacterium tuberculosis -sliding clamp is a protein essential for many important DNA transactions including replication and DNA repair proteins, thus, a potential drug target for tuberculosis. Further investigation is needed in understanding DNA polymerase sliding clamp structure, especially from a computational perspective. In this study, we employ a wide-range of comparative molecular dynamic analyses on two systems: Mycobacterium tuberculosis - sliding clamp enzyme in its apo and bound form. The results reported in this study shows apo conformation to be less stable, as compared to bound conformation with an average radius of gyration of 25.812 and 25.459 Å, respectively. This was further supported by root mean square fluctuation, where an apo enzyme showed a higher degree of flexibility. However, the presence of the ligand lowers radius of gyration and root mean square fluctuation and also leads to an existence of negative correlated motions. Principal component analysis further justifies the same findings, whereby the apo enzyme exhibits a higher fluctuation compared to the bound complex. In addition, a stable 310 helix located at the binding site appears to be unstable in the presence of the ligand. Hence, it is possible that the binding of the ligand may have caused a rearrangement of the structure, leading to a change in the unwinding of 310 helix. Findings reported in this study further enhance the understanding of Mycobacterium tuberculosis -DnaN and also give a lead to the development of potent tuberculosis drugs.

Single H5N1 influenza A neuraminidase mutation develops resistance to oseltamivir due to distorted conformational and drug binding landscape: multiple molecular dynamics analyses†

Clinical studies showed that a single mutation, I117V, develops severe resistance to oseltamivir, the first orally active influenza A neuraminidase inhibitor, in highly pathogenic H5N1 influenza A viruses. However the molecular mechanism by which this single mutation confers oseltamivir resistance is not well understood. Herein, and via “multiple” molecular dynamics approaches, we conducted a comparative study on the wild type and I117V mutant to understand the origin of resistance at the molecular level using a wide range of post-dynamics analytical tools. These include binding free energy calculations (MM/GBSA), principal component analysis (PCA), radius of gyration (RG), per-residue fluctuation (RMSF), solvent accessible surface area (SASA) and per-residue secondary structure occupancy. Results showed that single mutations at position 117 of H5N1 caused (1) distortion of the orientation of oseltamivir in the active site, (2) decrease in the binding affinity by ∼6 kcal mol−1 when compared to the wild type, (3) variation in the overall enzyme motion as evident from the PCA for both systems and (4) distortion of the hydrogen bonding network and atomic interactions with the inhibitor.

Anti-cancer glycosidase inhibitors from natural products: a computational and molecular modelling perspective.

The implementation of computational tools in pharmaceutics has proven an effectual strategy in creating harmony between the physical and chemical aspects of proteins and potential inhibitors. This is achieved by bringing to life the three dimensional retrospect of biological systems, which takes into consideration computational approaches such as quantum mechanics and molecular dynamics to facilitate drug design and discovery. In this work, we aim to provide a summary of the computational aspects of naturally derived anti-cancer inhibitors targeting the enzyme family of glycosidases. Our study offers insight into the evolution of drug discovery, molecular modelling and molecular binding modes of natural product inhibitors associated with glycosidase enzymes.

Dynamics of the thumb-finger regions in a GH11 xylanase Bacillus circulans : comparison between the Michaelis and covalent intermediate

The structure and dynamics of B. circulans β-1,4-xylanase (BCX) were comparatively studied utilizing molecular dynamics. Simulations of the free enzyme, non-covalently bound, and covalently bound xylobiose intermediate were conducted and post-dynamically studied to comprehend structural changes adopted during a reaction. Results showed that (a) covalent association of the substrate with the receptor induces a change in the structural conformation of the receptor; (b) the thumb region is highly flexible in the non-covalent complex compared to the covalent complex, drawing a conformational distinction between the two systems, a characteristic brought about by a more compact covalent complex structure in contrast to the non-covalent complex. This is most likely the result of a rigid covalent bond in addition to the hydrogen bond interactions between the substrate and receptor in the latter, (c) the distance between the thumb-finger residues Asp11-Pro116 is shortened upon substrate binding indicating that the flaps are drawn towards each other resulting in partial closing of the flaps. This study provides an invaluable contribution to the understanding of the dynamics of glycosidase enzymes which could largely contribute to the design of potent inhibitors targeting GH enzymes implicated in the orchestration of disease and disorders.

Re-emergence of an orphan therapeutic target for the treatment of resistant prostate cancer – a thorough conformational and binding analysis for ROR-γ protein

Recent studies have linked a deadly form of prostate cancer known as metastatic castration-resistant prostate cancer to retinoic acid-related orphan-receptor gamma (ROR-γ). Most of these studies continued to place ROR-γ as orphan because of unidentifiable inhibitor. Recently identified inhibitors of ROR-γ and their therapeutic potential were evaluated, among which inhibitor XY018 was the potent. However, molecular understanding of the conformational features of XY018-ROR-γ complex is still elusive. Herein, molecular dynamics simulations were conducted on HC9-ROR-γ and XY018-ROR-γ complexes to understand their conformational features at molecular level and the influence of XY018 binding on the dynamics of ROR-γ with the aid of post-dynamic analytical tools. These include; principal component analysis, radius of gyration, binding free energy calculation (MM/GBSA), per-residue fluctuation and hydrogen bond occupancy. Findings from this study revealed that (1) hydrophobic packing contributes significantly to binding free energy, (2) Ile136 and Leu60 exhibited high hydrogen-bond occupancy in XY018-ROR-γ and HC9-ROR-γ, respectively, (3) XY018-ROR-γ displayed a relatively high loop region residue fluctuation compared to HC9-ROR-γ, (4) electrostatic interactions are a potential binding force in XY018-ROR-γ complex compared to HC9-ROR-γ, (5) XY018-ROR-γ assumes a rigid conformation which is highlighted by a decrease in residual fluctuation, (6) XY018 could potentially induce pseudoporphyria, nephritis and interstitial nephritis but potentially safe in renal failure. This study could serve as a base line for the design of new potential ROR-γ inhibitors.

Review on the Biological Mechanisms Associated with Depo-Provera and HIV-1 Risk Acquisition in Women

Women constitute more than 50% out of millions of individuals infected with HIV-1, the major causative agent of acquired immune deficiency syndrome. About 40% of HIV-1 infections have been reported to initiate in the female reproductive tract. However, the mechanisms through which these infections are spread are poorly understood; hence, there is now a major concern in women who use long acting injectable hormonal contraceptives, particularly Depo-Provera and an increase of HIV-1 risk acquisition. Based on literature, Depo-Provera has an affinity for both the glucocorticoid receptor and the progesterone receptor in the female reproductive tract. Therefore, investigating HIV-1 pathogenesis in the female reproductive tract via the glucocorticoid receptor and the progesterone receptor mechanisms in response to the effect of Depo-Provera is of great importance.

Induced Mutation Proves a Potential Target for TB Therapy: A Molecular Dynamics Study on LprG

AbstractMolecular dynamics (MD) simulations of wild-type and V91W mutant Mycobacterium tuberculosis-LprG (Mtb-LprG) were performed with the goal to provide a comprehensive understanding of the Mtb-LprG as a potential antimycobacterial target. A long-range MD simulations and post-MD analyzes led us to various results that plainly explained the impact of V91W mutation on Mtb-LprG. Herein, the results revealed that the wild-type is less stable compared to V91W mutant. This was further supported by root mean square fluctuation, where the V91W mutant showed a higher degree of flexibility compared to the wild-type. Dynamic cross-correlation analysis revealed that induced mutation leads to higher residual flexibility in the mutant structure as compared to the wild-type structure thus resulting in the existence of negatively correlated motions. The difference in principal component analysis scatter plot across the first two normal modes suggests a greater mobility of the V91W mutant conformation compared to the wild-type. Thermodynamic calculations revealed that the van der Waals (Evdw) forces contribute the most towards binding free energy in a case of the V91W mutant as compared to the wild-type LprG complex. In addition, the residue interaction networks revealed more of Evdw interaction existence among residues in case of the V91W mutant. This study supports the Mtb-LprG as a potential antimycobacterial target and also serves as a cornerstone to identifying new potential targets that have no inhibitors.

Emergence of a Promising Lead Compound in the Treatment of Triple Negative Breast Cancer: An Insight into Conformational Features and Ligand Binding Landscape of c-Src Protein with UM-164

UM-164, a potent Src/p38 inhibitor, is a promising lead compound for developing the first targeted therapeutic strategy against triple-negative breast cancer (TNBC). However, lack of understanding of conformational features of UM-164 in complex with Src serves a challenge in the rational design of novel Src dual inhibitors. Herein, we provide an in-depth insight into conformational features of Src-UM-164 using different computational approaches. This involved molecular dynamics (MD) simulation, principal component analysis (PCA), thermodynamics calculations, dynamic cross-correlation (DCCM) analysis, and hydrogen bond formation. Findings from this study revealed that (1) the binding of UM-164 to Src induces a more stable and compact conformation; (2) the binding of UM-164 results in increased correlation among the active site residue; (3) the presence of multiple phenyl rings and fluorinated phenyl group in UM-164 contributes to the steric effect; (4) a relatively high-binding free energy estimated for the Src-UM-164 system is affirmative of its experimental potency; (5) hydrophobic packing contributes significantly to the drug binding in Src-UM-164; and (6) observed increase in H-bond distance of interacting residue atoms and Dasatinib compared to UM-164. Findings from this study can serve as a baseline in the design of novel Src inhibitors with dual inhibitory properties.