Fidele Ntie-Kang | Martin Luther University Halle-Wittenberg (original) (raw)
Papers by Fidele Ntie-Kang
Chemical papers/Chemické zvesti, Mar 14, 2024
Chemical prototypes with broad-spectrum antiviral activity are important toward developing new th... more Chemical prototypes with broad-spectrum antiviral activity are important toward developing new therapies that can act on both existing and emerging viruses. Binding of the SARS-CoV-2 spike protein to the host angiotensin-converting enzyme 2 (ACE2) receptor is required for cellular entry of SARS-CoV-2. Toward identifying new chemical leads that can disrupt this interaction, including in the presence of SARS-CoV-2 adaptive mutations found in variants like omicron that can circumvent vaccine, immune, and therapeutic antibody responses, we synthesized 5-chloro-3-(2-(2,4-dinitrophenyl)hydrazono) indolin-2-one (H 2 L) from the condensation reaction of 5-chloroisatin and 2,4-dinitrophenylhydrazine in good yield. H 2 L was characterised by elemental and spectral (IR, electronic, Mass) analyses. The NMR spectrum of H 2 L indicated a keto-enol tautomerism, with the keto form being more abundant in solution. H 2 L was found to selectively interfere with binding of the SARS-CoV-2 spike receptor-binding domain (RBD) to the host angiotensin-converting enzyme 2 receptor with a 50% inhibitory concentration (IC 50) of 0.26 μM, compared to an unrelated PD-1/PD-L1 ligand-receptor-binding pair with an IC 50 of 2.06 μM in vitro (Selectivity index = 7.9). Molecular docking studies revealed that the synthesized ligand preferentially binds within the ACE2 receptor-binding site in a region distinct from where spike mutations in SARS-CoV-2 variants occur. Consistent with these models, H 2 L was able to disrupt ACE2 interactions with the RBDs from beta, delta, lambda, and omicron variants with similar activities. These studies indicate that H 2 L-derived compounds are potential inhibitors of multiple SARS-CoV-2 variants, including those capable of circumventing vaccine and immune responses.
SDRP journal of computational chemistry & molecular modelling, 2022
New potent 3-dehydroquinic acid (AQs) inhibitors of 3-dehydroquinate dehydratase (dehydroquinase ... more New potent 3-dehydroquinic acid (AQs) inhibitors of 3-dehydroquinate dehydratase (dehydroquinase type II) of Mycobacterium tuberculosis (MtDHQ2) were obtained by using structure-based molecular design via the in situ modification of the template inhibitor AQ1 within the MtDHQ2-AQ1 crystal structure (PDB ID: 2XB8), in order to describe the interactions upon the formation of the complex MtDHQ2-inhibitor.
Molecules, Apr 29, 2020
Acquired Immunodeficiency Syndrome (AIDS), which chiefly originatesfroma retrovirus named Human I... more Acquired Immunodeficiency Syndrome (AIDS), which chiefly originatesfroma retrovirus named Human Immunodeficiency Virus (HIV), has impacted about 70 million people worldwide. Even though several advances have been made in the field of antiretroviral combination therapy, HIV is still responsible for a considerable number of deaths in Africa. The current antiretroviral therapies have achieved success in providing instant HIV suppression but with countless undesirable adverse effects. Presently, the biodiversity of the plant kingdom is being explored by several researchers for the discovery of potent anti-HIV drugs with different mechanisms of action. The primary challenge is to afford a treatment that is free from any sort of risk of drug resistance and serious side effects. Hence, there is a strong demand to evaluate drugs derived from plants as well as their derivatives. Several plants, such as Andrographis paniculata, Dioscorea bulbifera, Aegle marmelos, Wistaria floribunda, Lindera chunii, Xanthoceras sorbifolia and others have displayed significant anti-HIV activity. Here, weattempt to summarize the main results, which focus on the structures of most potent plant-based natural products having anti-HIV activity along with their mechanisms of action and IC 50 values, structure-activity-relationships and important key findings.
RSC Advances, 2017
Pyran is an oxygen-containing heterocyclic moiety, which exhibits an array of pharmacological pro... more Pyran is an oxygen-containing heterocyclic moiety, which exhibits an array of pharmacological properties. Pyran is also one of the important structural subunits found widely in natural products, e.g. coumarins, benzopyrans, sugars, flavonoids, xanthones, etc. The diverse anticancer capabilities of pyrans have been additionally evidenced by the fact that this heterocycle has recently been a focal point for researchers worldwide. This review provides a summary of pyran-based anticancer compounds, with emphasis on the past 10 years. It focuses on advancements in the field of naturally occurring pyrans as anticancer agents. The discussion also includes structure-activity relationships, along with the structures of the most promising molecules, their biological activities against several human cancer cell lines, as well as mechanistic insights discovered through the pharmacological evaluation and molecular modeling of pyran-based molecules. The promising activities revealed by these pyran-based scaffolds undoubtedly place them at the forefront for the discovery of prospective drug candidates. Thus, they could therefore be of great interest to researchers working on the synthesis of antitumour drug candidates.
SDRP Journal of Computational Chemistry & Molecular Modeling
New potent 3-dehydroquinic acid (AQs) inhibitors of 3-dehydroquinate dehydratase (dehydroquinase ... more New potent 3-dehydroquinic acid (AQs) inhibitors of 3-dehydroquinate dehydratase (dehydroquinase type II) of Mycobacterium tuberculosis (MtDHQ2) were obtained by using structure-based molecular design via the in situ modification of the template inhibitor AQ1 within the MtDHQ2-AQ1 crystal structure (PDB ID: 2XB8), in order to describe the interactions upon the formation of the complex MtDHQ2-inhibitor. A training set of 14 AQs with known inhibition constants (Kiexp) was used to establish a quantitative structure-activity relationship (QSAR) model for correlating the pKiexp (pKiexp = ‑log10 (Kiexp)) to the computed Gibbs free energies of formation (ΔΔGcom) of MtDHQ2-AQs complexes (pKiexp= -0.278 ΔΔGcom + 7.653 , R² = 0.98) is derived. This accounts for the solvent effect and the loss of inhibitor entropy upon enzyme binding. Validation of this QSAR model was performed with 3D- QSAR pharmacophore generation (PH4). The structural information derived from the 3D model and breakdown of c...
Fundamental Concepts, 2020
Additional file 1. List of journals consulted in building the initial data collection.
Additional file 1. Â MS data for synthesized compounds.
Additional file 2. Â NMR data for synthesized compounds (part 1).
Advanced Concepts and Applications, 2021
Physical Sciences Reviews, 2021
The use of molecular mechanics (MM) in understanding the energy and target of a drug, its structu... more The use of molecular mechanics (MM) in understanding the energy and target of a drug, its structures, and properties has increased recently. This is achieved by the formulation of a simple MM energy equation, which represents the sum of the different energy interactions, often referred to as “forcefields” (FFs). The concept of FFs is now widely used as one of the fundamental tools for the in silico prediction of drug-target interactions. To generate more accurate predictions in the in silico drug discovery projects, the solvent effects are often taken into account. This review seeks to present an introductory guide for the reader on the fundamentals of MM with special emphasis on the role of FFs and the solvation models.
Heliyon, 2021
A quantitative structure-activity relationship (QSAR) study was conducted using nineteen previous... more A quantitative structure-activity relationship (QSAR) study was conducted using nineteen previously synthesized, and tested 1-aryl-6-hydroxy-1,2,3,4-tetrahydroisoquinolines with proven in vitro activities against Plasmodium falciparum. In order to computationally design and screen potent antimalarial agents, these compounds with known biological activity ranging from 0.697 to 35.978 μM were geometry optimized at the B3LYP/6-311 + G(d,p) level of theory, using the Gaussian 09W software. To calculate the topological differences, the series of the nineteen compounds was superimposed and a hypermolecule obtained with s¯ = 17 and 20 vertices. Other molecular descriptors were considered in order to build a highly predictive QSAR model. These include the minimal topological differences (MTD), LogP, two dimensional polarity surface area (TDPSA), dipole moment (μ), chemical hardness (η), electrophilicity (ω), potential energy (Ep), electrostatic energy (Eele) and number of rotatable bonds (N...
Physical Sciences Reviews, 2021
In the quest to know why natural products (NPs) have often been considered as privileged scaffold... more In the quest to know why natural products (NPs) have often been considered as privileged scaffolds for drug discovery purposes, many investigations into the differences between NPs and synthetic compounds have been carried out. Several attempts to answer this question have led to the investigation of the atomic composition, scaffolds and functional groups (FGs) of NPs, in comparison with synthetic drugs analysis. This chapter briefly describes an atomic enumeration method for chemical libraries that has been applied for the analysis of NP libraries, followed by a description of the main differences between NPs of marine and terrestrial origin in terms of their general physicochemical properties, most common scaffolds and “drug-likeness” properties. The last parts of the work describe an analysis of scaffolds and FGs common in NP libraries, focusing on huge NP databases, e.g. those in the Dictionary of Natural Products (DNP), NPs from cyanobacteria and the largest chemical class of N...
Physical Sciences Reviews, 2021
Bacteria and fungi have a high potential to produce compounds that display large structural chang... more Bacteria and fungi have a high potential to produce compounds that display large structural change and diversity, thus displaying an extensive range of biological activities. Secondary metabolism or specialized metabolism is a term for pathways and small molecule products of metabolism that are not mandatory for the subsistence of the organism but improve and control their phenotype. Their interesting biological activities have occasioned their application in the fields of agriculture, food, and pharmaceuticals. Metabolic engineering is a powerful approach to improve access to these treasured molecules or to rationally engineer new ones. A thorough overview of engineering methods in secondary metabolism is presented, both in heterologous and epigenetic modification. Engineering methods to modify the structure of some secondary metabolite classes in their host are also intensively assessed.
The work presented in this thesis focuses on new natural product database tools and datasets for ... more The work presented in this thesis focuses on new natural product database tools and datasets for the discovery of lead compounds from African floral matter. Prior to the investigations, data regarding compounds which had been identified from the aforementioned sources were scattered in literature sources, some of which were inaccessible to the wider community of scientists. The resulting investigation has led to a collection of data on the constituent metabolites, their biological activities, as well as the uses of the source organisms in traditional medicine, which have been made available via the web. Moreover, the investigations have led to the identification (assisted and non assisted by molecular modeling) of lead compounds with anti-HIV, anti-Onchocerca, antiplasmodial, protease inhibitory and sirtuin inhibitory properties, beginning from plants with popular uses in African traditional medicine. The results presented in this thesis constitute the first outcome of computer-based investigation of the potential of African medicinal plants for drug discovery.
Advanced Concepts and Applications, 2021
Advanced Concepts and Applications, 2021
Computational Chemistry, 2021
Scientific African, 2021
Computational methods were used to filter two datasets (> 8,000 compounds) based on two criter... more Computational methods were used to filter two datasets (> 8,000 compounds) based on two criteria: higher binding affinity for MPRO than cocrystallized inhibitor and binding interactions with MPRO catalytic dyad (Cys145 and His41). After virtual screening involving ranking and reranking, eleven compounds were identified to satisfy these criteria and analysis of their structures revealed an unparallel common features among them which could be critical for their interactions with MPRO. However, only the topmost scoring compound (AV-203: K i = 0.31 µM) exhibited relatively stable binding interaction during the period of 50 ns MD simulation and thus is a suitable template for drug development.
Physical Sciences Reviews, 2020
The development and application of computer-aided drug design/discovery (CADD) techniques (such a... more The development and application of computer-aided drug design/discovery (CADD) techniques (such as structured-base virtual screening, ligand-based virtual screening and neural networks approaches) are on the point of disintermediation in the pharmaceutical drug discovery processes. The application of these CADD methods are standing out positively as compared to other experimental approaches in the identification of hits. In order to venture into new chemical spaces, research groups are exploring natural products (NPs) for the search and identification of new hits and more efficient leads as well as the repurposing of approved NPs. The chemical space of NPs is continuously increasing as a result of millions of years of evolution of species and these data are mainly stored in the form of databases providing access to scientists around the world to conduct studies using them. Investigation of these NP databases with the help of CADD methodologies in combination with experimental valida...
Chemical papers/Chemické zvesti, Mar 14, 2024
Chemical prototypes with broad-spectrum antiviral activity are important toward developing new th... more Chemical prototypes with broad-spectrum antiviral activity are important toward developing new therapies that can act on both existing and emerging viruses. Binding of the SARS-CoV-2 spike protein to the host angiotensin-converting enzyme 2 (ACE2) receptor is required for cellular entry of SARS-CoV-2. Toward identifying new chemical leads that can disrupt this interaction, including in the presence of SARS-CoV-2 adaptive mutations found in variants like omicron that can circumvent vaccine, immune, and therapeutic antibody responses, we synthesized 5-chloro-3-(2-(2,4-dinitrophenyl)hydrazono) indolin-2-one (H 2 L) from the condensation reaction of 5-chloroisatin and 2,4-dinitrophenylhydrazine in good yield. H 2 L was characterised by elemental and spectral (IR, electronic, Mass) analyses. The NMR spectrum of H 2 L indicated a keto-enol tautomerism, with the keto form being more abundant in solution. H 2 L was found to selectively interfere with binding of the SARS-CoV-2 spike receptor-binding domain (RBD) to the host angiotensin-converting enzyme 2 receptor with a 50% inhibitory concentration (IC 50) of 0.26 μM, compared to an unrelated PD-1/PD-L1 ligand-receptor-binding pair with an IC 50 of 2.06 μM in vitro (Selectivity index = 7.9). Molecular docking studies revealed that the synthesized ligand preferentially binds within the ACE2 receptor-binding site in a region distinct from where spike mutations in SARS-CoV-2 variants occur. Consistent with these models, H 2 L was able to disrupt ACE2 interactions with the RBDs from beta, delta, lambda, and omicron variants with similar activities. These studies indicate that H 2 L-derived compounds are potential inhibitors of multiple SARS-CoV-2 variants, including those capable of circumventing vaccine and immune responses.
SDRP journal of computational chemistry & molecular modelling, 2022
New potent 3-dehydroquinic acid (AQs) inhibitors of 3-dehydroquinate dehydratase (dehydroquinase ... more New potent 3-dehydroquinic acid (AQs) inhibitors of 3-dehydroquinate dehydratase (dehydroquinase type II) of Mycobacterium tuberculosis (MtDHQ2) were obtained by using structure-based molecular design via the in situ modification of the template inhibitor AQ1 within the MtDHQ2-AQ1 crystal structure (PDB ID: 2XB8), in order to describe the interactions upon the formation of the complex MtDHQ2-inhibitor.
Molecules, Apr 29, 2020
Acquired Immunodeficiency Syndrome (AIDS), which chiefly originatesfroma retrovirus named Human I... more Acquired Immunodeficiency Syndrome (AIDS), which chiefly originatesfroma retrovirus named Human Immunodeficiency Virus (HIV), has impacted about 70 million people worldwide. Even though several advances have been made in the field of antiretroviral combination therapy, HIV is still responsible for a considerable number of deaths in Africa. The current antiretroviral therapies have achieved success in providing instant HIV suppression but with countless undesirable adverse effects. Presently, the biodiversity of the plant kingdom is being explored by several researchers for the discovery of potent anti-HIV drugs with different mechanisms of action. The primary challenge is to afford a treatment that is free from any sort of risk of drug resistance and serious side effects. Hence, there is a strong demand to evaluate drugs derived from plants as well as their derivatives. Several plants, such as Andrographis paniculata, Dioscorea bulbifera, Aegle marmelos, Wistaria floribunda, Lindera chunii, Xanthoceras sorbifolia and others have displayed significant anti-HIV activity. Here, weattempt to summarize the main results, which focus on the structures of most potent plant-based natural products having anti-HIV activity along with their mechanisms of action and IC 50 values, structure-activity-relationships and important key findings.
RSC Advances, 2017
Pyran is an oxygen-containing heterocyclic moiety, which exhibits an array of pharmacological pro... more Pyran is an oxygen-containing heterocyclic moiety, which exhibits an array of pharmacological properties. Pyran is also one of the important structural subunits found widely in natural products, e.g. coumarins, benzopyrans, sugars, flavonoids, xanthones, etc. The diverse anticancer capabilities of pyrans have been additionally evidenced by the fact that this heterocycle has recently been a focal point for researchers worldwide. This review provides a summary of pyran-based anticancer compounds, with emphasis on the past 10 years. It focuses on advancements in the field of naturally occurring pyrans as anticancer agents. The discussion also includes structure-activity relationships, along with the structures of the most promising molecules, their biological activities against several human cancer cell lines, as well as mechanistic insights discovered through the pharmacological evaluation and molecular modeling of pyran-based molecules. The promising activities revealed by these pyran-based scaffolds undoubtedly place them at the forefront for the discovery of prospective drug candidates. Thus, they could therefore be of great interest to researchers working on the synthesis of antitumour drug candidates.
SDRP Journal of Computational Chemistry & Molecular Modeling
New potent 3-dehydroquinic acid (AQs) inhibitors of 3-dehydroquinate dehydratase (dehydroquinase ... more New potent 3-dehydroquinic acid (AQs) inhibitors of 3-dehydroquinate dehydratase (dehydroquinase type II) of Mycobacterium tuberculosis (MtDHQ2) were obtained by using structure-based molecular design via the in situ modification of the template inhibitor AQ1 within the MtDHQ2-AQ1 crystal structure (PDB ID: 2XB8), in order to describe the interactions upon the formation of the complex MtDHQ2-inhibitor. A training set of 14 AQs with known inhibition constants (Kiexp) was used to establish a quantitative structure-activity relationship (QSAR) model for correlating the pKiexp (pKiexp = ‑log10 (Kiexp)) to the computed Gibbs free energies of formation (ΔΔGcom) of MtDHQ2-AQs complexes (pKiexp= -0.278 ΔΔGcom + 7.653 , R² = 0.98) is derived. This accounts for the solvent effect and the loss of inhibitor entropy upon enzyme binding. Validation of this QSAR model was performed with 3D- QSAR pharmacophore generation (PH4). The structural information derived from the 3D model and breakdown of c...
Fundamental Concepts, 2020
Additional file 1. List of journals consulted in building the initial data collection.
Additional file 1. Â MS data for synthesized compounds.
Additional file 2. Â NMR data for synthesized compounds (part 1).
Advanced Concepts and Applications, 2021
Physical Sciences Reviews, 2021
The use of molecular mechanics (MM) in understanding the energy and target of a drug, its structu... more The use of molecular mechanics (MM) in understanding the energy and target of a drug, its structures, and properties has increased recently. This is achieved by the formulation of a simple MM energy equation, which represents the sum of the different energy interactions, often referred to as “forcefields” (FFs). The concept of FFs is now widely used as one of the fundamental tools for the in silico prediction of drug-target interactions. To generate more accurate predictions in the in silico drug discovery projects, the solvent effects are often taken into account. This review seeks to present an introductory guide for the reader on the fundamentals of MM with special emphasis on the role of FFs and the solvation models.
Heliyon, 2021
A quantitative structure-activity relationship (QSAR) study was conducted using nineteen previous... more A quantitative structure-activity relationship (QSAR) study was conducted using nineteen previously synthesized, and tested 1-aryl-6-hydroxy-1,2,3,4-tetrahydroisoquinolines with proven in vitro activities against Plasmodium falciparum. In order to computationally design and screen potent antimalarial agents, these compounds with known biological activity ranging from 0.697 to 35.978 μM were geometry optimized at the B3LYP/6-311 + G(d,p) level of theory, using the Gaussian 09W software. To calculate the topological differences, the series of the nineteen compounds was superimposed and a hypermolecule obtained with s¯ = 17 and 20 vertices. Other molecular descriptors were considered in order to build a highly predictive QSAR model. These include the minimal topological differences (MTD), LogP, two dimensional polarity surface area (TDPSA), dipole moment (μ), chemical hardness (η), electrophilicity (ω), potential energy (Ep), electrostatic energy (Eele) and number of rotatable bonds (N...
Physical Sciences Reviews, 2021
In the quest to know why natural products (NPs) have often been considered as privileged scaffold... more In the quest to know why natural products (NPs) have often been considered as privileged scaffolds for drug discovery purposes, many investigations into the differences between NPs and synthetic compounds have been carried out. Several attempts to answer this question have led to the investigation of the atomic composition, scaffolds and functional groups (FGs) of NPs, in comparison with synthetic drugs analysis. This chapter briefly describes an atomic enumeration method for chemical libraries that has been applied for the analysis of NP libraries, followed by a description of the main differences between NPs of marine and terrestrial origin in terms of their general physicochemical properties, most common scaffolds and “drug-likeness” properties. The last parts of the work describe an analysis of scaffolds and FGs common in NP libraries, focusing on huge NP databases, e.g. those in the Dictionary of Natural Products (DNP), NPs from cyanobacteria and the largest chemical class of N...
Physical Sciences Reviews, 2021
Bacteria and fungi have a high potential to produce compounds that display large structural chang... more Bacteria and fungi have a high potential to produce compounds that display large structural change and diversity, thus displaying an extensive range of biological activities. Secondary metabolism or specialized metabolism is a term for pathways and small molecule products of metabolism that are not mandatory for the subsistence of the organism but improve and control their phenotype. Their interesting biological activities have occasioned their application in the fields of agriculture, food, and pharmaceuticals. Metabolic engineering is a powerful approach to improve access to these treasured molecules or to rationally engineer new ones. A thorough overview of engineering methods in secondary metabolism is presented, both in heterologous and epigenetic modification. Engineering methods to modify the structure of some secondary metabolite classes in their host are also intensively assessed.
The work presented in this thesis focuses on new natural product database tools and datasets for ... more The work presented in this thesis focuses on new natural product database tools and datasets for the discovery of lead compounds from African floral matter. Prior to the investigations, data regarding compounds which had been identified from the aforementioned sources were scattered in literature sources, some of which were inaccessible to the wider community of scientists. The resulting investigation has led to a collection of data on the constituent metabolites, their biological activities, as well as the uses of the source organisms in traditional medicine, which have been made available via the web. Moreover, the investigations have led to the identification (assisted and non assisted by molecular modeling) of lead compounds with anti-HIV, anti-Onchocerca, antiplasmodial, protease inhibitory and sirtuin inhibitory properties, beginning from plants with popular uses in African traditional medicine. The results presented in this thesis constitute the first outcome of computer-based investigation of the potential of African medicinal plants for drug discovery.
Advanced Concepts and Applications, 2021
Advanced Concepts and Applications, 2021
Computational Chemistry, 2021
Scientific African, 2021
Computational methods were used to filter two datasets (> 8,000 compounds) based on two criter... more Computational methods were used to filter two datasets (> 8,000 compounds) based on two criteria: higher binding affinity for MPRO than cocrystallized inhibitor and binding interactions with MPRO catalytic dyad (Cys145 and His41). After virtual screening involving ranking and reranking, eleven compounds were identified to satisfy these criteria and analysis of their structures revealed an unparallel common features among them which could be critical for their interactions with MPRO. However, only the topmost scoring compound (AV-203: K i = 0.31 µM) exhibited relatively stable binding interaction during the period of 50 ns MD simulation and thus is a suitable template for drug development.
Physical Sciences Reviews, 2020
The development and application of computer-aided drug design/discovery (CADD) techniques (such a... more The development and application of computer-aided drug design/discovery (CADD) techniques (such as structured-base virtual screening, ligand-based virtual screening and neural networks approaches) are on the point of disintermediation in the pharmaceutical drug discovery processes. The application of these CADD methods are standing out positively as compared to other experimental approaches in the identification of hits. In order to venture into new chemical spaces, research groups are exploring natural products (NPs) for the search and identification of new hits and more efficient leads as well as the repurposing of approved NPs. The chemical space of NPs is continuously increasing as a result of millions of years of evolution of species and these data are mainly stored in the form of databases providing access to scientists around the world to conduct studies using them. Investigation of these NP databases with the help of CADD methodologies in combination with experimental valida...