In Silico Drug Repurposing Approach: Investigation of Mycobacterium tuberculosis FadD32 Targeted by FDA-Approved Drugs.

Background: Despite the enormous efforts made towards combating tuberculosis (TB), the disease remains a major global threat. Hence, new drugs with novel mechanisms against TB are urgently needed. Fatty acid degradation protein D32 (FadD32) has been identified as a promising drug target against TB, the protein is required for the biosynthesis of mycolic acids, hence, essential for the growth and multiplication of the mycobacterium. However, the FadD32 mechanism upon the binding of FDA-approved drugs is not well established. Herein, we applied virtual screening (VS), molecular docking, and molecular dynamic (MD) simulation to identify potential FDA-approved drugs against FadD32. Methodology/Results: VS technique was found promising to identify four FDA-approved drugs (accolate, sorafenib, mefloquine, and loperamide) with higher molecular docking scores, ranging from -8.0 to -10.0 kcal/mol. Post-MD analysis showed that the accolate hit displayed the highest total binding energy of -45.13 kcal/mol. Results also showed that the accolate hit formed more interactions with FadD32 active site residues and all active site residues displayed an increase in total binding contribution. RMSD, RMSF, Rg, and DCCM analysis further supported that the presence of accolate exhibited more structural stability, lower bimolecular flexibility, and more compactness into the FadD32 protein. Conclusions: Our study revealed accolate as the best potential drug against FadD32, hence a prospective anti-TB drug in TB therapy. In addition, we believe that the approach presented in the current study will serve as a cornerstone to identifying new potential inhibitors against a wide range of biological targets.

Ursolic acid as a potential inhibitor of Mycobacterium tuberculosis cytochrome bc1 oxidase-a molecular modelling perspective.

The escalating burden of tuberculosis disease and drastic effects of current medicine has stimulated a search for alternative drugs. A medicinal plant Warburgia salutaris has been reported to possess inhibitory properties against M. tuberculosis. In this study, we apply computational methods to investigate the probability of W. salutaris compounds as potential inhibitors of M. tuberculosis QcrB protein. We performed molecular docking, molecular dynamics simulations, radius of gyration, principal component analysis (PCA), and molecular mechanics-generalized born surface area (MM-GBSA) binding-free energy calculations in explicit solvent to achieve our objective. The results suggested that ursolic acid (UA) and ursolic acid acetate (UAA) could serve as preferred potential inhibitors of mycobacterial QcrB compared to lansoprazole sulphide (LSPZ) and telacebec (Q203)-UA and UAA have a higher binding affinity to QcrB compared to LSPZ and Q203 drugs. UA binding affinity is attributed to hydrogen bond formation with Val120, Arg364 and Arg366, and largely resonated from van der Waals forces resulting from UA interactions with hydrophobic amino acids in its vicinity. UAA binds to the porphyrin ring binding site with higher binding affinity compared to LSPZ. The binding affinity results primarily from van der Waals forces between UAA and hydrophobic residues of QcrB in the porphyrin ring binding site where UAA binds competitively. UA and UAA formed stable complexes with the protein with reduced overall residue mobility, consequently supporting the magnitude of binding affinity of the respective ligands. UAA could potentially compete with the porphyrin ring for the binding site and deprive the mycobacterial cell from oxygen, consequently disturbing mycobacterial oxygen-dependent metabolic processes. Therefore, discovery of a compound that competes with porphyrin ring for the binding site may be useful in QcrB pharmocological studies. UA proved to be a superior compound, although its estimated toxicity profile revealed UA to be hepatotoxic within acceptable parameters. Although preliminary findings of this report still warrant experimental validation, they could serve as a baseline for the development of new anti-tubercular drugs from natural resources that target QcrB.

Probing the dual inhibitory mechanisms of novel thiophenecarboxamide derivatives against Mycobacterium tuberculosis PyrG and PanK: an insight from biomolecular modeling study.

The growing occurrence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis (Mtb) strains underscores an urgent need for new antibiotics. The development of more bioactive antibiotics against drug-resistant organisms with a different mode of action could be a game-changer for the cure and eradication of tuberculosis (TB). Pantothenate Kinase (PanK) and CTP synthetase (PyrG) are both essential for RNA, DNA, and Lipids biosynthesis pathways. Given the extensive knowledge on these biosynthesis pathways inhibition of Mtb growth and survival, these enzymes present a fascinating opportunity for anti-mycobacterial drug discovery. Recently, it was experimentally established that the active metabolite 11426026 of compound 7947882 (a prodrug activated by EthA monooxygenase, 5-methyl-N-(4-nitrophenyl) thiophene-2-carboxamide) inhibits the activities of PyrG and PanK to indicate novel multitarget therapy aimed at discontinuing Mtb growth. However, the molecular mechanisms of their selective inhibition remain subtle. In this work, molecular dynamics simulations were employed to investigate the inhibitory mechanism as well as the selectivity impact of the active metabolite inhibitor of these enzymes. Computational modeling of the studied protein-ligand systems reveals that the active metabolite can potentially inhibit both PanK and PyrG, thereby creating a pathway as a double target approach in tuberculosis treatment.Communicated by Ramaswamy H. Sarma.

Computational studies of the properties and activities of selected trisubstituted benzimidazoles as potential antitubercular drugs inhibiting MTB-FtsZ polymerization.

Trisubstituted benzimidazoles (trisbenz) are significantly active against nonreplicating Mycobacterium tuberculosis (MTB) by inhibiting the polymerization of Filamentous Temperature Sensitive Mutant Z (FtsZ), an essential bacteria cell division protein. In-depth in-silico study of 5 of the most active trisubstituted benzimidazoles; trisbenz 1, 2, 3, 4 and 5, giving insight into their properties, such as stability, bioavailability, interactions with residues at the binding site of MTB-FtsZ and their influence on structural dynamics of the protein have been conducted. This was achieved through the application of in-silico methods including density functional theory (DFT) calculations, ADME properties calculations, molecular docking and molecular dynamics simulations. A DFT approach was applied to predict reactivity properties of potent FtsZ inhibitors, and the results reveal the relative reactivity of these inhibitors as bioactive moieties. The estimated ADME properties predicted all 5 compounds to be bioavailable and suitable for oral administration. Molecular docking, binding free energy, RMSD, RMSF, and hydrogen bond analysis confirmed these 5 compounds as potent MTB-FtsZ inhibitors. Although analyses proved these compounds to be bioactive and potent MTB-FtsZ inhibitors, however, trisbenz 1 appeared to be the most active against this protein while trisbenz 5 was the least active. This study further confirms the experimental study while also giving insight on the compounds mechanism of action and presents their bioavailability properties.

Identifying the analogues of berberine as promising antitubercular drugs targeting Mtb-FtsZ polymerisation through ligand-based virtual screening and molecular dynamics simulations.

Berberine, an active compound in the extract of golden seal (an age-long remedy for many infections) has been confirmed to be responsible for the extract's activity against multi-drug resistant strain of Mycobacterium tuberculosis. There is no available study that shows the exact target of berberine in M tuberculosis, although it is confirmed that berberine inhibits the polymerisation of filamentous temperature-sensitive mutant Z (FtsZ), an important bacteria cytokinesis protein, in Escherichia coli, suggesting that FtsZ could as well be the target of berberine in M tuberculosis. In this study, we carried out ligand-based virtual screening to identify analogues of berberine followed by molecular dynamics (MD) simulations of the complexes of Mtb-FtsZ with berberine (berb1) and the five selected analogues (berb9 [ZINC1709414], berb37 [ZINC238749993], berb38 [ZINC13509022], berb43 [ZINC14765594], and berb48 [ZINC238758595]). Post-MD analyses such as binding free energy, RMSD, RMSF, RoG and hydrogen bond lifetime analysis were used to understand the interactions between these ligands and the receptor. The results suggested that Mtb-FtsZ could likely be the target of berberine in M tuberculosis as it forms a stable complex coupled with a significantly high binding energy. The study also identified other potential inhibitors of MTB-FtsZ polymerisation. Berb38 specifically showed greater interaction with the residues at the binding site of the protein, forming a far more stable complex with the receptor than any of the other compounds under investigation, including berberine itself. ADME properties calculations also predicted all the ligands to be bioactive as orally administered drugs.

Drug Discovery for Mycobacterium tuberculosis Using Structure-Based Computer-Aided Drug Design Approach.

Developing new, more effective antibiotics against resistant Mycobacterium tuberculosis that inhibit its essential proteins is an appealing strategy for combating the global tuberculosis (TB) epidemic. Finding a compound that can target a particular cavity in a protein and interrupt its enzymatic activity is the crucial objective of drug design and discovery. Such a compound is then subjected to different tests, including clinical trials, to study its effectiveness against the pathogen in the host. In recent times, new techniques, which involve computational and analytical methods, enhanced the chances of drug development, as opposed to traditional drug design methods, which are laborious and time-consuming. The computational techniques in drug design have been improved with a new generation of software used to develop and optimize active compounds that can be used in future chemotherapeutic development to combat global tuberculosis resistance. This review provides an overview of the evolution of tuberculosis resistance, existing drug management, and the design of new anti-tuberculosis drugs developed based on the contributions of computational techniques. Also, we show an appraisal of available software and databases on computational drug design with an insight into the application of this software and databases in the development of anti-tubercular drugs. The review features a perspective involving machine learning, artificial intelligence, quantum computing, and CRISPR combination with available computational techniques as a prospective pathway to design new anti-tubercular drugs to combat resistant tuberculosis.

Characterization of an Atypical Trypanosoma brucei Hsp70 Demonstrates Its Cytosolic-Nuclear Localization and Modulation by Quercetin and Methylene Blue.

Trypanosoma brucei (Tb) harbours twelve Hsp70 chaperones. Of these, four are predicted to reside in the parasite cytosol. TbHsp70.c is predicted to be cytosolic and upregulated upon heat stress and is an ATPase that exhibits holdase chaperone function. Cytosol-localized Tbj2 stimulates the ATPase activity of TbHsp70.c. In the current study, immunofluorescence confirmed that TbHsp70.c is both a cytosolic and a nuclear protein. Furthermore, in silico analysis was used to elucidate an atypical linker and hydrophobic pocket. Tellingly, TbHsp70.c lacks the EEVD and GGMP motifs, both of which are implicated in substrate selectivity and co-chaperone binding in canonical Hsp70s. Far western analysis revealed that TbSTi1 interacts directly with TbHsp70 and TbHsp70.4, but does not bind TbHsp70.c. We further investigated the effect of quercetin and methylene blue on the Tbj2-driven ATPase activity of TbHsp70.c. We established that quercetin inhibited, whilst methylene blue enhanced, the Tbj2-stimulated ATPase activity of TbHsp70.c. Furthermore, these inhibitors were lethal to parasites. Lastly, we used molecular docking to show that quercetin and methylene blue may bind the nucleotide binding pocket of TbHsp70.c. Our findings suggest that small molecule inhibitors that target TbHsp70.c could be developed to serve as possible drug candidates against T. brucei.

A consequence of drug targeting of aminoacyl-tRNA synthetases in Mycobacteriumtuberculosis.

Drug-resistant Mycobacterium tuberculosis poses a great threat to public health and remains one of the red-flag tagged infectious diseases, with the tendency of comorbidity with other disease conditions such as HIV/AIDS. This perhaps is responsible for redoubling of effort in tuberculosis research and continuous change in patient management to optimize the drug therapy. Aminoacyl-tRNA synthetases are essential enzymes in M. tuberculosis that catalyse the transfer of a particular amino acid to its corresponding specific tRNA to form an aminoacyl-tRNA. These enzymes are believed to be novel antibacterial, antifungal and antiparasitic drug targets because of their role in the process of protein translation. Therefore, their existence as a compliment of M. tuberculosis has attracted a lot of research interest with the aim of curbing the scourge and provide the most effective drug in the treatment of tuberculosis. This leads to the discovery of a pool of aminoacyl-tRNA synthetases with their essential inhibitors. This review seeks to articulate the current advances in the development of new TB drugs exhibiting novelty in their mode of action with specific emphasis on aminoacyl-tRNA synthetases as drug targets.

Molecular Insights Into Di(2-Picolyl) Amine-Induced Cytotoxicity and Apoptosis in Human Kidney (HEK293) Cells.

Di(2-picolyl) amine (DPA) is a pyridine derivative known to chelate metal ions and thus has potential anticancer properties; however, its effect on normal cells remains unchartered necessitating further research. This study, therefore, investigated the mechanistic effects of DPA-induced cytotoxicity and apoptosis in the HEK293 cell line. Methods required that an half the maximum inhibition concentration (IC50) was derived using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Analyses aimed to assess oxidative stress, membrane damage, and DNA fragmentation by means of biochemical assays were performed. Luminometry analysis was carried out to understand the mechanism of apoptosis induction by determining the levels of adenosine triphosphate (ATP) and the activities of caspase-8, -9, and -3/7. Western blotting was used to ascertain the expression of apoptotic and stress-related proteins. An IC50 of 1,079 µM DPA was obtained. Antioxidant effect correlated with a minimum increase in reactive oxygen species induced lipid peroxidation. The increase in initiator caspase-8 and -9 and executioner caspase-3/7 activities by DPA-induced apoptosis albeit prompting a decline in the levels of ATP. Furthermore, DPA brought about the following consequences on HEK293 cells: markedly elevated tail lengths of the comets, poly (ADP-ribose) polymerase 1 cleavage, and apoptotic body formation observed in the late stages. The cytotoxic effects of DPA in HEK293 cells may be mediated by induction of apoptosis via the caspase-dependent mechanism.

Drug repurposing: Fusidic acid as a potential inhibitor of M. tuberculosis FtsZ polymerization - Insight from DFT calculations, molecular docking and molecular dynamics simulations.

Filamentous Temperature Sensitive Mutant Z (FtsZ), an important cell division protein in bacteria, has been validated as a potential target for antibiotics development. Citric acid has been found to inhibit the polymerization of Mycobacterium tuberculosis (MTB) FtsZ and several other drugs have been predicted as potential inhibitors through a gene ontology-based drug repurposing approach. An in-depth study on four of the predicted drugs; Fusidic acid (FusA), l-tryptophan, Carbamic acid, and 2-(3-guanidinophenyl)-3-mercaptopropanoic acid, as potential inhibitors of MTB-FtsZ polymerization was conducted using Citric acid as reference compound. The applied in silico methods involve DFT calculations, molecular docking and molecular dynamics simulations. DFT approach was applied to evaluate selectivity and stability properties of the predicted drugs. Calculated parameters including non-linear optical properties, charge distribution and electrostatic potential analyses enabled selectivity prediction of these potential drugs. DFT-based descriptors revealed FusA as the most potent compound, even more reactive than the referenced compound, Citric acid, which is also supported from the molecular docking study. Parameters including MM/PBSA binding free energies, RMSD, RMSF, RoG and hydrogen bond analysis also support FusA as the best potential MTB-FtsZ polymerization inhibitor, that forms a stable complex with the protein and impose greatest level of rigidity to the protein.

Understanding the Hsp90 N-terminal Dynamics: Structural and Molecular Insights into the Therapeutic Activities of Anticancer Inhibitors Radicicol (RD) and Radicicol Derivative (NVP-YUA922).

Heat shock protein 90 (Hsp90) is a crucial component in carcinogenesis and serves as a molecular chaperone that facilitates protein maturation whilst protecting cells against temperature-induced stress. The function of Hsp90 is highly dependent on adenosine triphosphate (ATP) binding to the N-terminal domain of the protein. Thus, inhibition through displacement of ATP by means of competitive binding with a suitable organic molecule is considered an attractive topic in cancer research. Radicicol (RD) and its derivative, resorcinylic isoxazole amine NVP-AUY922 (NVP), have shown promising pharmacodynamics against Hsp90 activity. To date, the underlying binding mechanism of RD and NVP has not yet been investigated. In this study, we provide a comprehensive understanding of the binding mechanism of RD and NVP, from an atomistic perspective. Density functional theory (DFT) calculations enabled the analyses of the compounds' electronic properties and results obtained proved to be significant in which NVP was predicted to be more favorable with solvation free energy value of -23.3 kcal/mol and highest stability energy of 75.5 kcal/mol for a major atomic delocalization. Molecular dynamic (MD) analysis revealed NVP bound to Hsp90 (NT-NVP) is more stable in comparison to RD (NT-RD). The Hsp90 protein exhibited a greater binding affinity for NT-NVP (-49.4 ± 3.9 kcal/mol) relative to NT-RD (-28.9 ± 4.5 kcal/mol). The key residues influential in this interaction are Gly 97, Asp 93 and Thr 184. These findings provide valuable insights into the Hsp90 dynamics and will serve as a guide for the design of potent novel inhibitors for cancer treatment.

Exploring the impact of H5N1 neuraminidase (H274Y) mutation on Peramivir: a bio-computational study from a molecular perspective.

Communicated by Ramaswamy H. Sarma.

A pre-test post-test assessment of non-invasive keratograph break up time and corneal epithelial thickness after vaping.

BACKGROUND: The effects of electronic cigarettes on the ocular surface has yet to be shown. The purpose of the study was to assess the impact of e-cigarette use on the anterior corneal surface integrity. METHODS: Forty three males and 21 females with an average of 21years were required to vape 0.05ml of e-liquid of 8mg nicotine concentration. Corneal epithelial thickness (CET) and Non Invasive Keratograph Tear Break up Time (NIKBUT) measurements were obtained prior to and post vaping. The Optovue iVue optical coherence topographer was used to measure central; superior; inferior; nasal and temporal CET and NIKBUT was assessed using the Oculus Keratograph 5M. RESULTS: There was a mean increase for central corneal epithelial thickness of 0.3448 microns. The superior CET increased by 0.2414 microns. The inferior CET increased by 0.2931microns. The nasal CET increased by 0.2069 microns. The temporal CET increased by 0.2759 microns. The mean change in NIKBUT post-vaping was an increase of 1.40 seconds. All observations occurred at p > 0.05. CONCLUSION: The acute effect of e-cigarette use does not impact corneal epithelial thickness and non-invasive keratography tear break up time after 10 puffs mild exposure but more research is needed to assess if this remains the case with more frequent, higher exposure.

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

Molecular 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.

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.

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.

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.

Tailored-pharmacophore model to enhance virtual screening and drug discovery: a case study on the identification of potential inhibitors against drug-resistant Mycobacterium tuberculosis (3R)-hydroxyacyl-ACP dehydratases.

AIM: Virtual screening (VS) is powerful tool in discovering molecular inhibitors that are most likely to bind to drug targets of interest. Herein, we introduce a novel VS approach, so-called 'tailored-pharmacophore', in order to explore inhibitors that overcome drug resistance. Methodology & results: The emergence and spread of drug resistance strains of tuberculosis is one of the most critical issues in healthcare. A tailored-pharmacophore approach was found promising to identify in silico predicted hit with better binding affinities in case of the resistance mutations in MtbHadAB as compared with thiacetazone, a prodrug used in the clinical treatment of tuberculosis. CONCLUSION: This approach can potentially be enforced for the discovery and design of drugs against a wide range of resistance targets.

The impact of Thr91 mutation on c-Src resistance to UM-164: molecular dynamics study revealed a new opportunity for drug design.

The emergence of a drug resistant non-receptor tyrosine kinase (c-Src) in triple-negative breast cancer (TNBC) remains a prime concern in relation to the burden of TNBC among people living with breast cancer and drug development. Thr91 mutation was found to induce a complete loss of protein conformation required for drug fitness. Herein, we provide the first account of the molecular impact of the Thr91 mutation on c-Src resistance to experimental drug UM-164 using various computational approaches, namely molecular dynamics simulation, principal component analysis (PCA), dynamic cross-correlation matrices (DCCM) analysis, hydrogen bond occupancy, thermodynamics calculation, ligand-residue interaction and residue interaction networks (RINs). Findings from this study revealed that Thr91 mutation leads to a steric conflict between UM-164 and the side chain of methionine (Met91); this mutation distorts the UM-164 optimum orientation on the conformational space of mutant c-Src compared to the wild-type; decreases hydrogen bond formation between the residues in the mutant protein structure; decreases the UM-164 binding energy in the mutant by -13.416 kcal mol-1; reduces the residue correlation in the mutant protein structure; induces a change in the overall protein structure conformation from an inactive to active conformation; and distorts the ligand atomic interaction network and the residue interaction network. This report provides important insights that will assist in the further design of novel dual kinase inhibitors to minimise the chances of drug resistance in triple negative breast cancer.

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.