The current study describes the construction of various ligand-based machine learning models to b... more The current study describes the construction of various ligand-based machine learning models to be used for drug-repurposing against the family of G-Protein Coupled Receptors (GPCRs). In building these models, we collected > 500,000 data points, encompassing experimentally measured molecular association data of > 160,000 unique ligands against > 250 GPCRs. These data points were retrieved from the GPCR-Ligand Association (GLASS) database. We have used diverse molecular featurization methods to describe the input molecules. Multiple supervised ML algorithms were developed, tested and compared for their accuracy, F scores, as well as for their Matthews’ correlation coefficient scores (MCC). Our data suggest that combined with molecular fingerprinting, ensemble decision trees and gradient boosted trees ML algorithms are on the accuracy border of the rather sophisticated deep neural nets (DNNs)-based algorithms. On a test dataset, these models displayed an excellent performance...
Replication of the SARS-CoV-2 genome is a fundamental step in the virus life cycle and inhibiting... more Replication of the SARS-CoV-2 genome is a fundamental step in the virus life cycle and inhibiting the SARS-CoV2 replicase machinery has been proven recently as a promising approach in combating the virus. Despite this recent success, there are still several aspects related to the structure, function and dynamics of the CoV-2 polymerase that still need to be addressed. This includes understanding the dynamicity of the various polymerase subdomains, analyzing the hydrogen bond networks at the active site and at the template entry in the presence of water, studying the binding modes of the nucleotides at the active site, highlighting positions for acceptable nucleotides’ substitutions that can be tolerated at different positions within the nascent RNA strand, identifying possible allosteric sites within the polymerase structure and studying their correlated dynamics relative to the catalytic site. Here, we combined various cutting-edge modelling tools with the recently resolved SARS-Co...
Blockade of the programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction... more Blockade of the programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction has emerged as a powerful strategy in cancer immunotherapy. Recently, there have been enormous efforts to develop potent PD-1/PD-L1 inhibitors. In particular, Bristol-Myers Squibb (BMS) and Aurigene Discovery Technologies have individually disclosed several promising PD-1/PD-L1 inhibitors, whose detailed experimental data are not publicly disclosed. In this work, we report the rigorous and systematic in vitro characterization of a selected set of potent PD-1/PD-L1 macrocyclic peptide (BMSpep-57) and small-molecule inhibitors (BMS-103, BMS-142) from BMS and a peptidomimetic small-molecule inhibitor from Aurigene (Aurigene-1) using a series of biochemical and cell-based assays. Our results confirm that BMS-103 and BMS-142 are strongly active in biochemical assays; however, their acute cytotoxicity greatly compromised their immunological activity. On the other hand, Aurigene-1 did not show any activity in both biochemical and immunological assays. Furthermore, we also report the discovery of a small-molecule immune modulator, whose mode-of-action is not clear; however, it exhibits favorable drug-like properties and strong immunological activity. We hope that the results presented here will be useful in guiding the development of next-generation PD-1/PD-L1 small molecule inhibitors. From the initial efforts of William Coley 1-3 , who demonstrated that treatment with live bacteria or bacterial products (Coley toxins) could regress tumors, in late 1800s to the recent Nobel Prize award to James Allison and Tasuku Honjo, for their discoveries of key immune checkpoints proteins 4 , cancer immunotherapy has come a long way. Today, immunotherapy has emerged as a powerful strategy for treating various types of cancers. This has become possible due to significant advances in our understanding about the molecular mechanisms behind the growth of cancers and their interplay with the host immune system, particularly the one mediated by T-lymphocytes (T cells). T cells play a pivotal role in controlling the adaptive immune response against pathogens 5 and in autoimmunity 6. Upon activation, T cells mediate various cellular immune responses against pathogens such as chronic viral infections 7-11. On the other hand, there is a class of negative immune modulatory molecules (called the
The voltage-gated KCNQ1 potassium ion channel interacts with the type I transmembrane protein min... more The voltage-gated KCNQ1 potassium ion channel interacts with the type I transmembrane protein minK (KCNE1) to generate the slow delayed rectifier (IKs) current in the heart. Mutations in these transmembrane proteins have been linked with several heart-related issues, including long QT syndromes (LQTS), congenital atrial fibrillation, and short QT syndrome. Off-target interactions of several drugs with that of KCNQ1/KCNE1 ion channel complex have been known to cause fatal cardiac irregularities. Thus, KCNQ1/KCNE1 remains an important avenue for drug-design and discovery research. In this work, we present the structural and mechanistic details of potassium ion permeation through an open KCNQ1 structural model using the combined molecular dynamics and steered molecular dynamics simulations. We discuss the processes and key residues involved in the permeation of a potassium ion through the KCNQ1 ion channel, and how the ion permeation is affected by (i) the KCNQ1-KCNE1 interactions and ...
The voltage-gated KCNQ1/KCNE1 potassium ion channel complex, forms the slow delayed rectifier (IK... more The voltage-gated KCNQ1/KCNE1 potassium ion channel complex, forms the slow delayed rectifier (IKs) current in the heart, which plays an important role in heart signaling. The importance of KCNQ1/KCNE1 channel's function is further implicated by the linkage between loss-of-function and gain-of-function mutations in KCNQ1 or KCNE1, and long QT syndromes, congenital atrial fibrillation, and short QT syndrome. Also, KCNQ1/KCNE1 channels are an off-target for many non-cardiovascular drugs, leading to fatal cardiac irregularities. One solution to address and study the mentioned aspects of KCNQ1/KNCE1 channel would be the structural studies using a validated and accurate model. Along the same line in this study, we have used several top-notch modeling approaches to build a structural model for the open state of KCNQ1 protein, which is both accurate and compatible with available experimental data. Next, we included the KCNE1 protein components using data-driven protein-protein docking ...
Applying atomistic computational modeling to drug discovery has proven to be a hugely successful ... more Applying atomistic computational modeling to drug discovery has proven to be a hugely successful approach, allowing drug-receptor interactions to be predicted and drugs to be optimized for potency, selectivity, and safety. However, when it comes to predicting protein-protein interactions and to rationally designing regulators of these interactions, computational tools often fail. Here, we report one of the rare instances where state-of-the-art computer simulations, guided by experiment, were able to correctly predict one of the most sophisticated protein-protein interactions. We revisit our previous discovery of the complex of human PD-1 with the ligand PD-L1 and compare our earlier findings with the recently published crystal structure of the same complex. Side-by-side comparison of the model of the complex with its crystal structure reveals outstanding agreement and suggests that our protein-protein prediction workflow could be applied to similar problems.
In the current study, we focused on the immune-checkpoints PD-1 pathway and in particular on the ... more In the current study, we focused on the immune-checkpoints PD-1 pathway and in particular on the ligand, PD-L1. We studied the conformational dynamics of PD-L1 through principal component analysis (PCA) of existing crystal structures combined with classical and accelerated molecular dynamics simulations. We identified the maximum structural displacements that take place in all PD-L1 crystal structures and in the MD trajectories. We found that these displacements are attributed to specific flexible regions in the protein. We also investigated the conformational preference for small molecule binding and highlighted a Methionine residue at the binding site, which plays a key role in drug binding. The binding mechanism of PD-L1 to other binding partners is also discussed in details from a computational perspective. We hope that the data presented here supports the ongoing efforts to discover effective therapies targeting the PD-1 immune-checkpoint pathway.
Direct-acting antivirals (DAAs) form the current standard of care (SOC) against hepatitis C virus... more Direct-acting antivirals (DAAs) form the current standard of care (SOC) against hepatitis C virus (HCV). These drugs selectively target the viral proteins, offering a unique mechanism to avoid toxicity, to increase their efficacy, and to evolve from decades of interferon- and ribavirin-based therapy. Among the promising HCV targets for DAAs is the NS5A protein, and daclatasvir (DCV) forms a first-in-class compound that selectively targets this protein. Despite the exceptional potency of DCV (∼picomolar IC50) and although several DCV derivatives have been approved for human use or are close to approval, the exact mode of action of these drugs is still incomplete. This is simply due to the vast complexity of cocrystallizing DCV with NS5A in the absence of two amphipathic helices that are required for DCV binding. In this context, computational modeling provides a unique alternative to solve this problem. Here, we build upon our recent discovery of a completely symmetrical interaction between DCV and NS5A and investigate the mode of binding of six other structures similar to DCV. The selected compounds include both symmetric and asymmetric molecules. In addition, we show that our model correlates very well with mutations that can confer resistance to DCV. The current study enhances our understanding of the mode of action of this class of HCV inhibitors and helps in defining the origen of resistance to these drugs.
Abnormalities in the human Nav1.5 (hNav1.5) voltage-gated sodium ion channel (VGSC) are associate... more Abnormalities in the human Nav1.5 (hNav1.5) voltage-gated sodium ion channel (VGSC) are associated with a wide range of cardiac problems and diseases in humans. Current structural models of hNav1.5 are still far from complete and, consequently, their ability to study atomistic interactions of this channel is very limited. Here, we report a comprehensive atomistic model of the hNav1.5 ion channel, constructed using homology modeling technique and refined through long molecular dynamics simulations (680 ns) in the lipid membrane bilayer. Our model was comprehensively validated by using reported mutagenesis data, comparisons with previous models, and binding to a panel of known hNav1.5 blockers. The relatively long classical MD simulation was sufficient to observe a natural sodium permeation event across the channel's selectivity filters to reach the channel's central cavity, together with the identification of a unique role of the lysine residue. Electrostatic potential calcul...
Beta-Caryophyllene (BCP), a naturally occurring sesquiterpene abundantly found in cloves, hops, a... more Beta-Caryophyllene (BCP), a naturally occurring sesquiterpene abundantly found in cloves, hops, and cannabis, is the active candidate of a relatively new group of vascular-inhibiting compounds that aim to block existing tumor blood vessels. Previously, we have reported the anti-cancer properties of BCP by utilizing a series of in-vitro anti-tumor-related assays using human colorectal carcinoma cells. The present study aimed to investigate the effects of BCP on in-vitro, ex-vivo, and in-vivo models of anti-angiogenic assays and evaluate its anti-cancer activity in xenograft tumor (both ectopic and orthotopic) mice models of human colorectal cancer. Computational structural analysis and an apoptosis antibody array were also performed to understand the molecular players underlying this effect. BCP exhibited strong anti-angiogenic activity by blocking the migration of endothelial cells, tube-like network formation, suppression of vascular endothelial growth factor (VEGF) secretion from ...
Journal of Enzyme Inhibition and Medicinal Chemistry
Pyridazine scaffolds are considered privileged structures pertaining to its novelty, chemical sta... more Pyridazine scaffolds are considered privileged structures pertaining to its novelty, chemical stability, and synthetic feasibility. In our quest towards the development of novel scaffolds for effective vascular endothelial growth 2 (VEGFR-2) inhibition with antiangiogenic activity, four novel series of pyridazines were designed and synthesised. Five of the synthesised compounds; namely (8c, 8f, 15, 18b, and 18c) exhibited potent VEGFR-2 inhibitory potency (>80%); with IC 50 values ranging from low micromolar to nanomolar range; namely compounds 8c, 8f, 15, 18c with (1.8 mM, 1.3 mM, 1.4 mM, 107 nM), respectively. Moreover, 3-[4-f(6-oxo-1,6-dihydropyridazin-3-yl)oxygphenyl]urea derivative (18b) exhibited nanomolar potency towards VEGFR-2 (60.7 nM). In cellular assay, the above compounds showed excellent inhibition of VEGF-stimulated proliferation of human umbilical vein endothelial cells at 10 lM concentration. Finally, an extensive molecular simulation study was performed to investigate the probable interaction with VEGFR-2.
Entropy of binding constitutes a major, and in many cases a detrimental, component of the binding... more Entropy of binding constitutes a major, and in many cases a detrimental, component of the binding affinity in biomolecular interactions. While the enthalpic part of the binding free energy is easier to calculate, estimating the entropy of binding is further more complicated. A precise evaluation of entropy requires a comprehensive exploration of the complete phase space of the interacting entities. As this task is extremely hard to accomplish in the context of conventional molecular simulations, calculating entropy has involved many approximations. Most of these golden standard methods focused on developing a reliable estimation of the conformational part of the entropy. Here, we review these methods with a particular emphasis on the different techniques that extract entropy from atomic fluctuations. The theoretical formalisms behind each method is explained highlighting its strengths as well as its limitations, followed by a description of a number of case studies for each method. We hope that this brief, yet comprehensive, review provides a useful tool to understand these methods and realize the practical issues that may arise in such calculations.
Soft X-ray photoelectron spectroscopy has been used to investigate the radiosensitizer nimorazole... more Soft X-ray photoelectron spectroscopy has been used to investigate the radiosensitizer nimorazole and related model compounds. We report the valence and C, N, and O 1s photoemission spectra and K-edge NEXAFS spectra of gas-phase nimorazole, 1-methyl-5-nitroimidazole, and 4(5)-nitroimidazole in combination with theoretical calculations. The valence band and core level spectra are in agreement with theory. We determine the equilibrium populations of the two tautomers in 4(5)-nitroimidazole and find a ratio of 1:0.7 at 390 K. The NEXAFS spectra of the studied nitroimidazoles show excellent agreement with spectra of compounds available in the literature that exhibit a similar chemical environment. By comparing 1-methyl-5-nitroimidazole (single tautomer) with 4(5)-nitroimidazole, we are able to disentangle the photoemission and photoabsorption spectra and identify features due to each single tautomer.
Chikungunya virus (CHIKV) is a mosquito-borne alphavirus. Recent outbreaks of CHIKV infections ha... more Chikungunya virus (CHIKV) is a mosquito-borne alphavirus. Recent outbreaks of CHIKV infections have been reported in Asia, Africa and Europe. The symptoms of CHIKV infection include fever, headache, nausea, vomiting, myalgia, rash and chronic persistent arthralgia. To date, no vaccines or selective anti-viral drugs against this important emerging virus have been reported. In the current study, the design, synthesis and antiviral activity screening of new topographical peptidomimetics revealed three potential prototype agents3a, 4b and 5d showing 93- 100 % maximum inhibition of CHIKV replication in cell based assay having EC90 of 8.76 - 9.57 μg /mL. Intensive molecular modeling studies including covalent docking, LUMO energies and the atomic condensed Fukui functions calculations strongly suggested the covalent binding ofpeptidomimetics3a, 4b and 5dto CHIKV nsP2 proteaseleading to permanent enzyme inactivation via Michael adduct formation between α/β unsaturated ketone functionality ...
Quantum mechanics study of β–lactam and alanine through gamma-ray and graph theory combined with ... more Quantum mechanics study of β–lactam and alanine through gamma-ray and graph theory combined with C1s binding energy and nuclear magnetic resonance (NMR) Chatterjee S1, Ahmed M 1, Wang F 1*, Ganesan A1, Prince K2, Feyer V2 and Plekan O2 Presenting author’s e-mail: subhojyotichatterjee@swin.edu.au 1 Faculty of Science, Engineering and Technology and Molecular Model Discovery Laboratory, Swinburne University of Technology, Victoria, Australia. 2Sincrotrone Trieste in Area Science Park, Trieste, Italy For decades, the fact that the mode of action of β–lactam antibiotics involves competition with the alanyl-alanine moiety was incompletely understood. In this study, the molecular structure and X-ray spectra of the basic entity of both the β–lactam antibiotic which is the β–lactam ring and the alanyl-alanine which is the alanine amino acid are compared. Although the molecular structures are apparently different, analysing the X-ray spectra on the light of DFT based calculations shows certa...
X-ray photoemission spectroscopy of radiosensitizers Mayanthi Goonewardanea, Linda Feketeováb, Ma... more X-ray photoemission spectroscopy of radiosensitizers Mayanthi Goonewardanea, Linda Feketeováb, Marawan Ahmeda, Feng Wanga*, Kevin C. Princea,c and Michael R. Horsmand aMolecular Model Discovery Laboratory, Faculty of Science, Engineering and Technology, Swinburne University of Technology, Hawthorn, Melbourne, Victoria, 3122, Australia bSchool of Chemistry and Bio21 Institute of Molecular Science and Biotechnology, The University of Melbourne, Victoria 3010, Australia cSincrotrone Trieste, in Area Science Park, I-34149 Basovizza, Trieste, Italy dDepartment of Experimental Clinical Oncology, Aarhus University Hospital, Denmark *Corresponding author, email: fwang@swin.edu.au Abstract: Radiosensitizers are used in radiotherapy to enhance tumour control of radioresistant hypoxic tumours. Recent studies indicate that the formation of radical anions is a key step. Thus understanding the ionization reactions of radiosensitizers is crucial in evaluating the radiosensitization potential and i...
The current study describes the construction of various ligand-based machine learning models to b... more The current study describes the construction of various ligand-based machine learning models to be used for drug-repurposing against the family of G-Protein Coupled Receptors (GPCRs). In building these models, we collected > 500,000 data points, encompassing experimentally measured molecular association data of > 160,000 unique ligands against > 250 GPCRs. These data points were retrieved from the GPCR-Ligand Association (GLASS) database. We have used diverse molecular featurization methods to describe the input molecules. Multiple supervised ML algorithms were developed, tested and compared for their accuracy, F scores, as well as for their Matthews’ correlation coefficient scores (MCC). Our data suggest that combined with molecular fingerprinting, ensemble decision trees and gradient boosted trees ML algorithms are on the accuracy border of the rather sophisticated deep neural nets (DNNs)-based algorithms. On a test dataset, these models displayed an excellent performance...
Replication of the SARS-CoV-2 genome is a fundamental step in the virus life cycle and inhibiting... more Replication of the SARS-CoV-2 genome is a fundamental step in the virus life cycle and inhibiting the SARS-CoV2 replicase machinery has been proven recently as a promising approach in combating the virus. Despite this recent success, there are still several aspects related to the structure, function and dynamics of the CoV-2 polymerase that still need to be addressed. This includes understanding the dynamicity of the various polymerase subdomains, analyzing the hydrogen bond networks at the active site and at the template entry in the presence of water, studying the binding modes of the nucleotides at the active site, highlighting positions for acceptable nucleotides’ substitutions that can be tolerated at different positions within the nascent RNA strand, identifying possible allosteric sites within the polymerase structure and studying their correlated dynamics relative to the catalytic site. Here, we combined various cutting-edge modelling tools with the recently resolved SARS-Co...
Blockade of the programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction... more Blockade of the programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction has emerged as a powerful strategy in cancer immunotherapy. Recently, there have been enormous efforts to develop potent PD-1/PD-L1 inhibitors. In particular, Bristol-Myers Squibb (BMS) and Aurigene Discovery Technologies have individually disclosed several promising PD-1/PD-L1 inhibitors, whose detailed experimental data are not publicly disclosed. In this work, we report the rigorous and systematic in vitro characterization of a selected set of potent PD-1/PD-L1 macrocyclic peptide (BMSpep-57) and small-molecule inhibitors (BMS-103, BMS-142) from BMS and a peptidomimetic small-molecule inhibitor from Aurigene (Aurigene-1) using a series of biochemical and cell-based assays. Our results confirm that BMS-103 and BMS-142 are strongly active in biochemical assays; however, their acute cytotoxicity greatly compromised their immunological activity. On the other hand, Aurigene-1 did not show any activity in both biochemical and immunological assays. Furthermore, we also report the discovery of a small-molecule immune modulator, whose mode-of-action is not clear; however, it exhibits favorable drug-like properties and strong immunological activity. We hope that the results presented here will be useful in guiding the development of next-generation PD-1/PD-L1 small molecule inhibitors. From the initial efforts of William Coley 1-3 , who demonstrated that treatment with live bacteria or bacterial products (Coley toxins) could regress tumors, in late 1800s to the recent Nobel Prize award to James Allison and Tasuku Honjo, for their discoveries of key immune checkpoints proteins 4 , cancer immunotherapy has come a long way. Today, immunotherapy has emerged as a powerful strategy for treating various types of cancers. This has become possible due to significant advances in our understanding about the molecular mechanisms behind the growth of cancers and their interplay with the host immune system, particularly the one mediated by T-lymphocytes (T cells). T cells play a pivotal role in controlling the adaptive immune response against pathogens 5 and in autoimmunity 6. Upon activation, T cells mediate various cellular immune responses against pathogens such as chronic viral infections 7-11. On the other hand, there is a class of negative immune modulatory molecules (called the
The voltage-gated KCNQ1 potassium ion channel interacts with the type I transmembrane protein min... more The voltage-gated KCNQ1 potassium ion channel interacts with the type I transmembrane protein minK (KCNE1) to generate the slow delayed rectifier (IKs) current in the heart. Mutations in these transmembrane proteins have been linked with several heart-related issues, including long QT syndromes (LQTS), congenital atrial fibrillation, and short QT syndrome. Off-target interactions of several drugs with that of KCNQ1/KCNE1 ion channel complex have been known to cause fatal cardiac irregularities. Thus, KCNQ1/KCNE1 remains an important avenue for drug-design and discovery research. In this work, we present the structural and mechanistic details of potassium ion permeation through an open KCNQ1 structural model using the combined molecular dynamics and steered molecular dynamics simulations. We discuss the processes and key residues involved in the permeation of a potassium ion through the KCNQ1 ion channel, and how the ion permeation is affected by (i) the KCNQ1-KCNE1 interactions and ...
The voltage-gated KCNQ1/KCNE1 potassium ion channel complex, forms the slow delayed rectifier (IK... more The voltage-gated KCNQ1/KCNE1 potassium ion channel complex, forms the slow delayed rectifier (IKs) current in the heart, which plays an important role in heart signaling. The importance of KCNQ1/KCNE1 channel's function is further implicated by the linkage between loss-of-function and gain-of-function mutations in KCNQ1 or KCNE1, and long QT syndromes, congenital atrial fibrillation, and short QT syndrome. Also, KCNQ1/KCNE1 channels are an off-target for many non-cardiovascular drugs, leading to fatal cardiac irregularities. One solution to address and study the mentioned aspects of KCNQ1/KNCE1 channel would be the structural studies using a validated and accurate model. Along the same line in this study, we have used several top-notch modeling approaches to build a structural model for the open state of KCNQ1 protein, which is both accurate and compatible with available experimental data. Next, we included the KCNE1 protein components using data-driven protein-protein docking ...
Applying atomistic computational modeling to drug discovery has proven to be a hugely successful ... more Applying atomistic computational modeling to drug discovery has proven to be a hugely successful approach, allowing drug-receptor interactions to be predicted and drugs to be optimized for potency, selectivity, and safety. However, when it comes to predicting protein-protein interactions and to rationally designing regulators of these interactions, computational tools often fail. Here, we report one of the rare instances where state-of-the-art computer simulations, guided by experiment, were able to correctly predict one of the most sophisticated protein-protein interactions. We revisit our previous discovery of the complex of human PD-1 with the ligand PD-L1 and compare our earlier findings with the recently published crystal structure of the same complex. Side-by-side comparison of the model of the complex with its crystal structure reveals outstanding agreement and suggests that our protein-protein prediction workflow could be applied to similar problems.
In the current study, we focused on the immune-checkpoints PD-1 pathway and in particular on the ... more In the current study, we focused on the immune-checkpoints PD-1 pathway and in particular on the ligand, PD-L1. We studied the conformational dynamics of PD-L1 through principal component analysis (PCA) of existing crystal structures combined with classical and accelerated molecular dynamics simulations. We identified the maximum structural displacements that take place in all PD-L1 crystal structures and in the MD trajectories. We found that these displacements are attributed to specific flexible regions in the protein. We also investigated the conformational preference for small molecule binding and highlighted a Methionine residue at the binding site, which plays a key role in drug binding. The binding mechanism of PD-L1 to other binding partners is also discussed in details from a computational perspective. We hope that the data presented here supports the ongoing efforts to discover effective therapies targeting the PD-1 immune-checkpoint pathway.
Direct-acting antivirals (DAAs) form the current standard of care (SOC) against hepatitis C virus... more Direct-acting antivirals (DAAs) form the current standard of care (SOC) against hepatitis C virus (HCV). These drugs selectively target the viral proteins, offering a unique mechanism to avoid toxicity, to increase their efficacy, and to evolve from decades of interferon- and ribavirin-based therapy. Among the promising HCV targets for DAAs is the NS5A protein, and daclatasvir (DCV) forms a first-in-class compound that selectively targets this protein. Despite the exceptional potency of DCV (∼picomolar IC50) and although several DCV derivatives have been approved for human use or are close to approval, the exact mode of action of these drugs is still incomplete. This is simply due to the vast complexity of cocrystallizing DCV with NS5A in the absence of two amphipathic helices that are required for DCV binding. In this context, computational modeling provides a unique alternative to solve this problem. Here, we build upon our recent discovery of a completely symmetrical interaction between DCV and NS5A and investigate the mode of binding of six other structures similar to DCV. The selected compounds include both symmetric and asymmetric molecules. In addition, we show that our model correlates very well with mutations that can confer resistance to DCV. The current study enhances our understanding of the mode of action of this class of HCV inhibitors and helps in defining the origen of resistance to these drugs.
Abnormalities in the human Nav1.5 (hNav1.5) voltage-gated sodium ion channel (VGSC) are associate... more Abnormalities in the human Nav1.5 (hNav1.5) voltage-gated sodium ion channel (VGSC) are associated with a wide range of cardiac problems and diseases in humans. Current structural models of hNav1.5 are still far from complete and, consequently, their ability to study atomistic interactions of this channel is very limited. Here, we report a comprehensive atomistic model of the hNav1.5 ion channel, constructed using homology modeling technique and refined through long molecular dynamics simulations (680 ns) in the lipid membrane bilayer. Our model was comprehensively validated by using reported mutagenesis data, comparisons with previous models, and binding to a panel of known hNav1.5 blockers. The relatively long classical MD simulation was sufficient to observe a natural sodium permeation event across the channel's selectivity filters to reach the channel's central cavity, together with the identification of a unique role of the lysine residue. Electrostatic potential calcul...
Beta-Caryophyllene (BCP), a naturally occurring sesquiterpene abundantly found in cloves, hops, a... more Beta-Caryophyllene (BCP), a naturally occurring sesquiterpene abundantly found in cloves, hops, and cannabis, is the active candidate of a relatively new group of vascular-inhibiting compounds that aim to block existing tumor blood vessels. Previously, we have reported the anti-cancer properties of BCP by utilizing a series of in-vitro anti-tumor-related assays using human colorectal carcinoma cells. The present study aimed to investigate the effects of BCP on in-vitro, ex-vivo, and in-vivo models of anti-angiogenic assays and evaluate its anti-cancer activity in xenograft tumor (both ectopic and orthotopic) mice models of human colorectal cancer. Computational structural analysis and an apoptosis antibody array were also performed to understand the molecular players underlying this effect. BCP exhibited strong anti-angiogenic activity by blocking the migration of endothelial cells, tube-like network formation, suppression of vascular endothelial growth factor (VEGF) secretion from ...
Journal of Enzyme Inhibition and Medicinal Chemistry
Pyridazine scaffolds are considered privileged structures pertaining to its novelty, chemical sta... more Pyridazine scaffolds are considered privileged structures pertaining to its novelty, chemical stability, and synthetic feasibility. In our quest towards the development of novel scaffolds for effective vascular endothelial growth 2 (VEGFR-2) inhibition with antiangiogenic activity, four novel series of pyridazines were designed and synthesised. Five of the synthesised compounds; namely (8c, 8f, 15, 18b, and 18c) exhibited potent VEGFR-2 inhibitory potency (>80%); with IC 50 values ranging from low micromolar to nanomolar range; namely compounds 8c, 8f, 15, 18c with (1.8 mM, 1.3 mM, 1.4 mM, 107 nM), respectively. Moreover, 3-[4-f(6-oxo-1,6-dihydropyridazin-3-yl)oxygphenyl]urea derivative (18b) exhibited nanomolar potency towards VEGFR-2 (60.7 nM). In cellular assay, the above compounds showed excellent inhibition of VEGF-stimulated proliferation of human umbilical vein endothelial cells at 10 lM concentration. Finally, an extensive molecular simulation study was performed to investigate the probable interaction with VEGFR-2.
Entropy of binding constitutes a major, and in many cases a detrimental, component of the binding... more Entropy of binding constitutes a major, and in many cases a detrimental, component of the binding affinity in biomolecular interactions. While the enthalpic part of the binding free energy is easier to calculate, estimating the entropy of binding is further more complicated. A precise evaluation of entropy requires a comprehensive exploration of the complete phase space of the interacting entities. As this task is extremely hard to accomplish in the context of conventional molecular simulations, calculating entropy has involved many approximations. Most of these golden standard methods focused on developing a reliable estimation of the conformational part of the entropy. Here, we review these methods with a particular emphasis on the different techniques that extract entropy from atomic fluctuations. The theoretical formalisms behind each method is explained highlighting its strengths as well as its limitations, followed by a description of a number of case studies for each method. We hope that this brief, yet comprehensive, review provides a useful tool to understand these methods and realize the practical issues that may arise in such calculations.
Soft X-ray photoelectron spectroscopy has been used to investigate the radiosensitizer nimorazole... more Soft X-ray photoelectron spectroscopy has been used to investigate the radiosensitizer nimorazole and related model compounds. We report the valence and C, N, and O 1s photoemission spectra and K-edge NEXAFS spectra of gas-phase nimorazole, 1-methyl-5-nitroimidazole, and 4(5)-nitroimidazole in combination with theoretical calculations. The valence band and core level spectra are in agreement with theory. We determine the equilibrium populations of the two tautomers in 4(5)-nitroimidazole and find a ratio of 1:0.7 at 390 K. The NEXAFS spectra of the studied nitroimidazoles show excellent agreement with spectra of compounds available in the literature that exhibit a similar chemical environment. By comparing 1-methyl-5-nitroimidazole (single tautomer) with 4(5)-nitroimidazole, we are able to disentangle the photoemission and photoabsorption spectra and identify features due to each single tautomer.
Chikungunya virus (CHIKV) is a mosquito-borne alphavirus. Recent outbreaks of CHIKV infections ha... more Chikungunya virus (CHIKV) is a mosquito-borne alphavirus. Recent outbreaks of CHIKV infections have been reported in Asia, Africa and Europe. The symptoms of CHIKV infection include fever, headache, nausea, vomiting, myalgia, rash and chronic persistent arthralgia. To date, no vaccines or selective anti-viral drugs against this important emerging virus have been reported. In the current study, the design, synthesis and antiviral activity screening of new topographical peptidomimetics revealed three potential prototype agents3a, 4b and 5d showing 93- 100 % maximum inhibition of CHIKV replication in cell based assay having EC90 of 8.76 - 9.57 μg /mL. Intensive molecular modeling studies including covalent docking, LUMO energies and the atomic condensed Fukui functions calculations strongly suggested the covalent binding ofpeptidomimetics3a, 4b and 5dto CHIKV nsP2 proteaseleading to permanent enzyme inactivation via Michael adduct formation between α/β unsaturated ketone functionality ...
Quantum mechanics study of β–lactam and alanine through gamma-ray and graph theory combined with ... more Quantum mechanics study of β–lactam and alanine through gamma-ray and graph theory combined with C1s binding energy and nuclear magnetic resonance (NMR) Chatterjee S1, Ahmed M 1, Wang F 1*, Ganesan A1, Prince K2, Feyer V2 and Plekan O2 Presenting author’s e-mail: subhojyotichatterjee@swin.edu.au 1 Faculty of Science, Engineering and Technology and Molecular Model Discovery Laboratory, Swinburne University of Technology, Victoria, Australia. 2Sincrotrone Trieste in Area Science Park, Trieste, Italy For decades, the fact that the mode of action of β–lactam antibiotics involves competition with the alanyl-alanine moiety was incompletely understood. In this study, the molecular structure and X-ray spectra of the basic entity of both the β–lactam antibiotic which is the β–lactam ring and the alanyl-alanine which is the alanine amino acid are compared. Although the molecular structures are apparently different, analysing the X-ray spectra on the light of DFT based calculations shows certa...
X-ray photoemission spectroscopy of radiosensitizers Mayanthi Goonewardanea, Linda Feketeováb, Ma... more X-ray photoemission spectroscopy of radiosensitizers Mayanthi Goonewardanea, Linda Feketeováb, Marawan Ahmeda, Feng Wanga*, Kevin C. Princea,c and Michael R. Horsmand aMolecular Model Discovery Laboratory, Faculty of Science, Engineering and Technology, Swinburne University of Technology, Hawthorn, Melbourne, Victoria, 3122, Australia bSchool of Chemistry and Bio21 Institute of Molecular Science and Biotechnology, The University of Melbourne, Victoria 3010, Australia cSincrotrone Trieste, in Area Science Park, I-34149 Basovizza, Trieste, Italy dDepartment of Experimental Clinical Oncology, Aarhus University Hospital, Denmark *Corresponding author, email: fwang@swin.edu.au Abstract: Radiosensitizers are used in radiotherapy to enhance tumour control of radioresistant hypoxic tumours. Recent studies indicate that the formation of radical anions is a key step. Thus understanding the ionization reactions of radiosensitizers is crucial in evaluating the radiosensitization potential and i...
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