Rational Drug Design Approach Research Articles

Abstract LB036: Back and forth from structure to functional target: The interplay between Vimentin and non-canonical nucleic acid arrangements

Abstract Vimentin, a member of type III intermediate filaments (IFs), is a cytoskeletal protein that covers multiple architectural and functional roles, including the maintenance of organelle positioning in the cytoplasm, the regulation of cytoskeletal rearrangements, while more recently its potential involvement as a regulatory factor in gene expression emerged. Additionally, it is involved in cell migration and epithelial-to-mesenchymal transition (EMT). In previous works, we identified Vimentin as the first known protein that selectively binds G-quadruplexes repeats (G4-repeats). This DNA folding consists of repeated units of nucleic acid sequences arranged into G-quadruplex (G4s). Their three-dimensional features largely differ from the most common single-stranded or double-helix nucleic acids as well as from the isolated G4 modules. Noteworthy, they occur at a small subset of genomic sites, associated with cell proliferation and migration, where they can recruit the soluble nuclear pool of Vimentin. Altogether, this information led us to consider the Vimentin-DNA complex as a promising target for developing small molecule binders capable of inhibiting cell migration and, eventually, EMT. To properly set up a rational drug-design approach, we integrated different advanced biophysical tools (Hydrogen-Deuterium Exchange, Cryo-Electron Microscopy) to derive a comprehensive picture of the protein-DNA complex at the molecular level. This approach allowed us to map the interaction surface between the soluble tetrameric form of Vimentin and a G4-repeat. Based on this data, we initiated a screening campaign using focused libraries of small molecules and peptides, which were rationally designed according to the structural features of the Vimentin-G4-repeats complex. The capability of the identified hits to prevent the recognition of the nucleic acid by Vimentin has been investigated This approach allowed us to identify attractive novel entities that prevent the Vimentin-G4-repeat complex formation according to different molecular mechanisms. These systems are now under further refinement moving from the test tube to the cellular environment, where the dynamic behavior of these nucleic acid domains as well as the recruitment of different proteins by Vimentin might alter the architectural features of the target.

Biological New Targets Prediction & ADME Pharmacokinetics Profiling of Newly Synthesized E / Z Isomers of Methyl 2-phenyl-2-(2-phenylhydrazono) Acetate Derivatives

Objective: In order to predict the pharmacokinetic properties, and new potential biological targets, biological targets prediction, and absorption, distribution, metabolism and excretion (ADME) profiling of newly synthesized Entgegen / Zusammen (E / Z isomers) of Methyl 2-phenyl-2-(2-phenylhydrazono) acetate derivatives were carried out. Methods: The prediction of new biological targets, pharmacokinetic properties, membrane permeability, and bioavailability radar properties were carried out by using Swiss Targets Prediction and Swiss ADME tools, respectively. Results: All the eight screened compounds possessed excellent drug-likeness criteria and passed successfully from Pan-assay interference compounds filter. Additionally, all screened compounds fell within the acceptable range in the bioavailability radar, showing excellent descriptors with a slight exceeding of insaturation properties. Compounds displayed elevated permeability across the Blood Brain Barrier, while compounds exhibited highest Human Intestinal Absorption according to the Egan Egg model. Moreover, the screened compounds also exhibited good pharmacokinetic properties. All the compounds exhibited activity against various enzymes, such as lyase, kinase, protease, and Family AG protein-coupled receptor. Conclusion: This conducted study smartly reveals that in-silico based studies were considered to provide robustness towards a rational drug design and development approach; therefore, in this way, it helps for further investigation of drug design and drug discovery steps.

Ligand coupling mechanism of the human serotonin transporter differentiates substrates from inhibitors

The presynaptic serotonin transporter (SERT) clears extracellular serotonin following vesicular release to ensure temporal and spatial regulation of serotonergic signalling and neurotransmitter homeostasis. Prescription drugs used to treat neurobehavioral disorders, including depression, anxiety, and obsessive-compulsive disorder, trap SERT by blocking the transport cycle. In contrast, illicit drugs of abuse like amphetamines reverse SERT directionality, causing serotonin efflux. Both processes result in increased extracellular serotonin levels. By combining molecular dynamics simulations with biochemical experiments and using a homologous series of serotonin analogues, we uncovered the coupling mechanism between the substrate and the transporter, which triggers the uptake of serotonin. Free energy analysis showed that only scaffold-bound substrates could initiate SERT occlusion through attractive long-range electrostatic interactions acting on the bundle domain. The associated spatial requirements define substrate and inhibitor properties, enabling additional possibilities for rational drug design approaches.

Implementation of multi-criteria decision making for the ranking of drugs used to treat bone-cancer

<abstract> <p>The concept of "topological index" refers to a numerical value determined by the structure of a chemical network. It serves to determine the physicochemical and biological properties of diverse medications, offering a more precise depiction of the theoretical properties of organic materials, this is achieved through the utilization of degree-based topological indices. Because of the development of resistance to existing treatments and the unpleasant side effects associated with some current drugs, the hunt for new drugs remains a priority. In drug discovery, QSPR approaches are widely used to predict, from a chemical structure, the biological activity of potential novel drugs. Researchers can prioritize compounds for synthesis and optimize them to improve potency, preference, and other desired attributes by establishing a correlation between chemical features and biological activity. Rational drug design approaches incorporate research methodologies such as quantitative structure-activity relationships (QSAR) and quantitative structure-property relationships (QSPR), along with decision-making strategies. The goal of these strategies is to improve the biological activity and physicochemical qualities of existing leads. This research includes mathematical modeling of drug mechanisms utilizing multiple-criteria decision analysis and QSPR analysis. Furthermore, using decision-making techniques, I can determine the order of production for various drugs used to treat bone cancer based on their examination using QSPR analysis and topological indices.</p> </abstract>

Design, synthesis and preclinical evaluation of muscarine receptor antagonists via a scaffold-hopping approach

Our research group recently identified a rearrangement product of pirenzepine as starting point for a comprehensive rational drug design approach towards orthosteric muscarinic acetylcholine receptor ligands. Chemical reduction and bioscaffold hop lead to the development of sixteen promising compounds featuring either a benzimidazole or carbamate moiety, all exhibiting comparable pharmacophoric characteristics. The synthesized compounds were characterized by NMR, HR-MS, and RP-HPLC techniques. Subsequent evaluation encompassed binding affinity assessment on CHO-hM1-5 cells, mode of action determination, and analysis of physico-chemical parameters. The CNS MPO score indicated favorable drug-like attributes and potential CNS activity for the antagonistic ligands. The most promising compounds displayed Ki-values within a desirable low nanomolar range, and their structural features allow for potential carbon-11 radiolabeling. Our optimization efforts resulted in compounds with a remarkable 138-fold increase in binding affinity compared to the previously mentioned rearrangement product towards human M5, suggesting their prospective utility in positron emission tomography applications.

In Silico and In Vitro Potential of FDA-Approved Drugs for Antimalarial Drug Repurposing against Plasmodium Serine Hydroxymethyltransferases.

Malaria has spread in many countries, with a 12% increase in deaths after the coronavirus disease 2019 pandemic. Malaria is one of the most concerning diseases in the Greater Mekong subregion, showing increased drug-resistant rates. Serine hydroxymethyltransferase (SHMT), a key enzyme in the deoxythymidylate synthesis pathway, has been identified as a promising antimalarial drug target due to its conserved folate binding pocket. This study used a molecular docking approach to screen 2509 US Food and Drug Administration (FDA)-approved drugs against seven Plasmodium SHMT structures. Eight compounds had significantly lower binding energies than the known SHMT inhibitors pyrazolopyran(+)-86, tetrahydrofolate, and antimalarial drugs, ranging from 4 to 10 kcal/mol. Inhibition assays testing the eight compounds against Plasmodium falciparum SHMT (PfSHMT) showed that amphotericin B was a competitive inhibitor of PfSHMT with a half-maximal inhibitory concentration (IC50) of 106 ± 1 μM. Therefore, a 500 ns molecular dynamics simulation of PfSHMT/PLS/amphotericin B was performed. The backbone root-mean-square deviation of the protein-ligand complex indicated the high complex stability during simulations, supported by its radius of gyration, hydrogen-bond interactions, and number of atom contacts. The appreciable binding affinity of amphotericin B for PfSHMT was indicated by their solvated interaction energy (-11.15 ± 0.09 kcal/mol) and supported by strong ligand-protein interactions (≥80% occurrences) with its essential residues (i.e., Y78, K151, N262, F266, and V365) predicted by pharmacophore modeling and per-residue decomposition free energy methods. Therefore, our findings identify a promising new PfSHMT inhibitor, albeit with less inhibitory activity, and suggest a core structure that differs from that of previous SHMT inhibitors, thus being a rational approach for novel antimalarial drug design.

Small molecule targeting of transcription-replication conflict for selective chemotherapy

Targeting transcription replication conflicts, a major source of endogenous DNA double-stranded breaks and genomic instability could have important anticancer therapeutic implications. Proliferating cell nuclear antigen (PCNA) is critical to DNA replication and repair processes. Through a rational drug design approach, we identified a small molecule PCNA inhibitor, AOH1996, which selectively kills cancer cells. AOH1996 enhances the interaction between PCNA and the largest subunit of RNA polymerase II, RPB1, and dissociates PCNA from actively transcribed chromatin regions, while inducing DNA double-stranded breaks in a transcription-dependent manner. Attenuation of RPB1 interaction with PCNA, by a point mutation in RPB1's PCNA-binding region, confers resistance to AOH1996. Orally administrable and metabolically stable, AOH1996 suppresses tumor growth as a monotherapy or as a combination treatment but causes no discernable side effects. Inhibitors of transcription replication conflict resolution may provide a new and unique therapeuticavenue for exploiting this cancer-selective vulnerability.

Design, synthesis, and evaluation of novel benzoylhydrazone derivatives as Nur77 modulators with potent antitumor activity against hepatocellular carcinoma

Nur77 modulators have emerged as a promising therapeutic approach for hepatocellular carcinoma. In this study, a structure-based rational drug design approach was used to design and synthesise a series of 4-((8-hydroxy-2-methylquinolin-4-yl)amino)benzoylhydrazone derivatives based on the binding characteristics of our previously reported 10g and the native ligand 3NB at the binding Site C of Nur77. Cell-based cytotoxicity assays revealed that compound TMHA37 demonstrated the highest cytotoxicity against all tested cancer cells. The induced fit docking and binding pose metadynamics simulation suggested that TMHA37 was the most promising Nur77 binder at Site C. Molecular dynamics simulation validated the stable binding of TMHA37 to Nur77’s Site C but not to Sites A or B. Specifically, TMHA37 bound strongly to Nur77-LBD (K D = 445.3 nM) and could activate Nur77’s transcriptional activity. Furthermore, TMHA37 exhibited antitumor effects by blocking the cell cycle at G2/M phase and inducing cell apoptosis in a Nur77-dependent manner.

The crosstalk between the RNA demethylase, non‐coding RNAs, and transcription factors in gastric cancer: An ALKBH5 perspective

The crosstalk between the RNA demethylase, non‐coding RNAs, and transcription factors in gastric cancer: An ALKBH5 perspective

Cyclohexane-1,3-dione Derivatives as Future Therapeutic Agents for NSCLC: QSAR Modeling, In Silico ADME-Tox Properties, and Structure-Based Drug Designing Approach.

The abnormal expression of the c-Met tyrosine kinase has been linked to the proliferation of several human cancer cell lines, including non-small-cell lung cancer (NSCLC). In this context, the identification of new c-Met inhibitors based on heterocyclic small molecules could pave the way for the development of a new cancer therapeutic pathway. Using multiple linear regression (MLR)-quantitative structure-activity relationship (QSAR) and artificial neural network (ANN)-QSAR modeling techniques, we look at the quantitative relationship between the biological inhibitory activity of 40 small molecules derived from cyclohexane-1,3-dione and their topological, physicochemical, and electronic properties against NSCLC cells. In this regard, screening methods based on QSAR modeling with density-functional theory (DFT) computations, in silico pharmacokinetic/pharmacodynamic (ADME-Tox) modeling, and molecular docking with molecular electrostatic potential (MEP) and molecular mechanics-generalized Born surface area (MM-GBSA) computations were used. Using physicochemical (stretch-bend, hydrogen bond acceptor, Connolly molecular area, polar surface area, total connectivity) and electronic (total energy, highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy levels) molecular descriptors, compound 6d is identified as the optimal scaffold for drug design based on in silico screening tests. The computer-aided modeling developed in this study allowed us to design, optimize, and screen a new class of 36 small molecules based on cyclohexane-1,3-dione as potential c-Met inhibitors against NSCLC cell growth. The in silico rational drug design approach used in this study led to the identification of nine lead compounds for NSCLC therapy via c-Met protein targeting. Finally, the findings are validated using a 100 ns series of molecular dynamics simulations in an aqueous environment on c-Met free and complexed with samples of the proposed lead compounds and Foretinib drug.

Predictions of the Poses and Affinity of a Ligand over the Entire Surface of a NEET Protein: The Case of Human MitoNEET.

Human NEET proteins contain two [2Fe-2S] iron-sulfur clusters, bound to three Cys residues and one His residue. They exist in two redox states. Recently, these proteins have revealed themselves as attractive drug targets for mitochondrial dysfunction-related diseases, such as type 2 diabetes, Wolfram syndrome 2, and cancers. Unfortunately, the lack of information and mechanistic understanding of ligands binding to the whole functional, cytoplasmatic domain has limited rational drug design approaches. Here, we use an enhanced sampling technique, volume-based metadynamics, recently developed by a team involving some of us, to predict the poses and affinity of the 2-benzamido-4-(1,2,3,4-tetrahydronaphthalen-2-yl)-thiophene-3-carboxylate ligand to the entire surface of the cytoplasmatic domain of the human NEET protein mitoNEET (mNT) in an aqueous solution. The calculations, based on the recently published X-ray structure of the complex, are consistent with the measured affinity. The calculated free energy landscape revealed that the ligand can bind in multiple sites and with poses other than the one found in the X-ray. This difference is likely to be caused by crystal packing effects that allow the ligand to interact with multiple adjacent NEET protein copies. Such extra contacts are of course absent in the solution; therefore, the X-ray pose is only transient in our calculations, where the binding free energy correlates with the number of contacts. We further evaluated how the reduction and protonation of the Fe-bound histidine, as well as temperature, can affect ligand binding. Both such modifications introduce the possibility for the ligand to bind in an area of the protein other than the one observed in the X-ray, with no or little impact on affinity. Overall, our study can provide insights on the molecular recognition mechanisms of ligand binding to mNT in different oxidative conditions, possibly helping rational drug design of NEET ligands.

Identification of macrocyclic peptides which activate bacterial cylindrical proteases.

The caseinolytic protease complex ClpXP is an important house-keeping enzyme in prokaryotes charged with the removal and degradation of misfolded and aggregated proteins and performing regulatory proteolysis. Dysregulation of its function, particularly by inhibition or allosteric activation of the proteolytic core ClpP, has proven to be a promising strategy to reduce virulence and eradicate persistent bacterial infections. Here, we report a rational drug-design approach to identify macrocyclic peptides which increase proteolysis by ClpP. This work expands the understanding of ClpP dynamics and sheds light on the conformational control exerted by its binding partner, the chaperone ClpX, by means of a chemical approach. The identified macrocyclic peptide ligands may, in the future, serve as a starting point for the development of ClpP activators for antibacterial applications.

Ruthenium Metallotherapeutics: Novel Approaches to Combatting Parasitic Infections.

Human parasitic infections cause a combined global mortality rate of over one million people per annum and represent some of the most challenging diseases for medical intervention. Current chemotherapeutic strategies often require prolonged treatment, coupled with subsequent drug-induced cytotoxic morbidity to the host, while resistance generation is also a major concern. Metals have been used extensively throughout the history of medicine, with more recent applications as anticancer and antimicrobial agents. Ruthenium metallotherapeutic antiparasitic agents are highly effective at targeting a range of key parasites, including the causative agents of malaria, trypanosomiasis, leishmaniasis, amoebiasis, toxoplasmosis and other orphan diseases, while demonstrating lower cytotoxicity profiles than current treatment strategies. Generally, such compounds also demonstrate activity against multiple cellular target sites within parasites, including inhibition of enzyme function, cell membrane perturbation, and alterations to metabolic pathways, therefore reducing the opportunity for resistance generation. This review provides a comprehensive and subjective analysis of the rapidly developing area of ruthenium metal- based antiparasitic chemotherapeutics, in the context of rational drug design and potential clinical approaches to combatting human parasitic infections.

Machine learning-based predictive modeling, virtual screening and biological evaluation studies for identification of potential inhibitors of MMP-13

Matrix Metalloproteinase-13 (MMP-13) is a collagenase that regulates the homeostasis of the extracellular matrix (ECM) and basement membrane, as well as the breakdown of type II collagen. Recent research studies on the molecular and cellular mechanisms of cartilage degradation suggest that MMP-13 overexpression triggers osteoarthritis and is considered a promising target for osteoarthritis treatment. The present work employs machine learning-based virtual screening and structure-based rational drug design approaches to identify potential inhibitors of MMP-13 with diverse chemical scaffolds. The twelve top-scoring screened compounds were subjected to biological evaluation to validate the robustness and predictive modeling of ML-based Virtual Screening. It was observed that eight compounds exhibited approximately 44%–60% inhibition at 0.1 µM concentration, and the IC50 lies in the range of 1.9–2.3 µM against MMP-13. Interestingly, two of the compounds, DP01473 and RH01617, showed potent dose-dependent inhibitory activity. Compound DP01473 inhibited MMP-13 by 44%, 50%, and 70%, while compound RH01617 inhibited MMP-13 by 54%, 55%, and 57% at 0.1 μM, 1 μM, and 10 μM concentrations, respectively, and can be further optimized for the design and development of more potent MMP-13 inhibitors. Communicated by Ramaswamy H. Sarma

Design, Synthesis, and Biological Characterization of Inhaled p38α/β MAPK Inhibitors for the Treatment of Lung Inflammatory Diseases.

The identification of novel inhaled p38α/β mitogen-activated protein kinases (MAPK) (MAPK14/11) inhibitors suitable for the treatment of pulmonary inflammatory conditions has been described. A rational drug design approach started from the identification of a novel tetrahydronaphthalene series, characterized by nanomolar inhibition of p38α with selectivity over p38γ and p38δ isoforms. SAR optimization of 1c is outlined, where improvements in potency against p38α and ligand-enzyme dissociation kinetics led to several compounds showing pronounced anti-inflammatory effects in vitro (inhibition of TNFα release). Targeting of the defined physicochemical properties allowed the identification of compounds 3h, 4e, and 4f, which showed, upon intratracheal instillation, low plasma levels, prolonged lung retention, and anti-inflammatory effects in a rat acute model of a bacterial endotoxin-induced pulmonary inflammation. Compound 4e, in particular, displayed remarkable efficacy and duration of action and was selected for progression in disease models of asthma and chronic obstructive pulmonary disease (COPD).

Crystal structures of pertussis toxin with NAD+ and analogs provide structural insights into the mechanism of its cytosolic ADP-ribosylation activity

Bordetella pertussis is the causative agent of whooping cough, a highly contagious respiratory disease. Pertussis toxin (PT), a major virulence factor secreted by B. pertussis, is an AB5-type protein complex topologically related to cholera toxin. The PT protein complex is internalized by host cells and follows a retrograde trafficking route to the endoplasmic reticulum, where it subsequently dissociates. The released enzymatic S1 subunit is then translocated from the endoplasmic reticulum into the cytosol and subsequently ADP-ribosylates the inhibitory alpha-subunits (Gαi) of heterotrimeric G proteins, thus promoting dysregulation of G protein–coupled receptor signaling. However, the mechanistic details of the ADP-ribosylation activity of PT are not well understood. Here, we describe crystal structures of the S1 subunit in complex with nicotinamide adenine dinucleotide (NAD+), with NAD+ hydrolysis products ADP-ribose and nicotinamide, with NAD+ analog PJ34, and with a novel NAD+ analog formed upon S1 subunit crystallization with 3-amino benzamide and NAD+, which we name benzamide amino adenine dinucleotide. These crystal structures provide unprecedented insights into pre- and post-NAD+ hydrolysis steps of the ADP-ribosyltransferase activity of PT. We propose that these data may aid in rational drug design approaches and further development of PT-specific small-molecule inhibitors.

Design, synthesis, and biological evaluation of some methyl 2-(1H-pyrazol-4-ylthio)-1,2,3,4-tetrahydro-6-methylpyrimidine-5-carboxylate derivatives as potential DHFR inhibitors

Drug-resistant bacteria pose an increasingly serious threat to mankind all over the world. However, the currently available clinical treatments do not meet the urgent demand. Therefore, it is desirable to find new targets and inhibitors to overcome the problems of antibiotic resistance. Dihydrofolate reductase (DHFR) is an important enzyme required to maintain bacterial growth, and hence inhibitors of DHFR have been proven as effective agents for treating bacterial infections. In the present work, we have designed some methyl 2-(1H-pyrazol-4-ylthio)-1,2,3,4-tetrahydro-6-methylpyrimidine-5-carboxylate derivatives as potential DHFR inhibitors through rational drug design approach. The designed derivatives were screened through Lipinski rule, Veber’s rule, ADMET analysis, drug-likeness properties, and molecular docking. All the compounds demonstrated more potent activity than Ampicillin against both gram-positive and gram-negative bacteria. Most of the compounds were more or equipotent than Chloramphenicol and Ciprofloxacin. Compound A7 was sensitive at 25 µg/mL against Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus whereas compound A20 was sensitive to all gram +ve and –ve bacteria at same concentration. Compound A16 was sensitive at 50 µg/mL against all the bacteria. In antifungal activity, compound A7 exhibited MFCs of 100 µg/mL against Candida albicans, Aspergillus niger, and Aspergillus clavatus which is same as Nystatin.

Potential Biological Targets Prediction, ADME Profiling, and Molecular Docking Studies of Novel Steroidal Products from Cunninghamella blakesleana.

New potential biological targets prediction through inverse molecular docking technique is another smart strategy to forecast the possibility of compounds being biologically active against various target receptors. In this case of designed study, we screened our recently obtained novel acetylenic steroidal biotransformed products [(1) 8-β-methyl-14-α-hydroxyΔ4tibolone (2) 9-α-HydroxyΔ4 tibolone (3) 8-β-methyl-11-β-hydroxyΔ4tibolone (4) 6-β-hydroxyΔ4tibolone, (5) 6-β-9-α-dihydroxyΔ4tibolone (6) 7-β-hydroxyΔ4tibolone)] from fungi Cunninghemella Blakesleana to predict their possible biological targets and profiling of ADME properties. The prediction of pharmacokinetic properties, membrane permeability, and bioavailability radar properties was carried out by using Swiss target prediction and Swiss ADME tools, respectively. These metabolites were also subjected to predict the possible mechanism of action along with associated biological network pathways by using Reactome database. All the six screened compounds possessed excellent drug ability criteria and exhibited exceptionally excellent non-inhibitory potential against all five isozymes of the CYP450 enzyme complex, including CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4. All the screened compounds are lying within the acceptable pink zone of bioavailability radar and showing excellent descriptive properties. Compounds [1-4 & 6] are showing high BBB (Blood Brain Barrier) permeation, while compound 5 is exhibiting high HIA (Human Intestinal Absorption) property of (Egan Egg). In conclusion, the results of this study smartly reveal that in-silico based studies are considered to provide robustness towards a rational drug design and development approach; therefore, in this way, it helps to avoid the possibility of failure of drug candidates in the later experimental stages of drug development phases.

Rational drug design, synthesis, and biological evaluation of novel N-(2-arylaminophenyl)-2,3-diphenylquinoxaline-6-sulfonamides as potential antimalarial, antifungal, and antibacterial agents

ObjectiveSulfanilamide, sulfadiazine, and dapsone were the first sulfonamides to be used to treat malaria by disrupting the folate biosynthesis process, which is essential for parasite survival. Therefore, we aimed to synthesize novel N-(2-arylaminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide derivatives through a rational drug design approach. MethodsAll compounds were synthesized by the conventional method, and the products were characterized by spectral analysis (1H NMR and mass spectrometry). The progression of the reaction was monitored using thin-layer chromatography (TLC). All the derivatives were analyzed for their effective binding mode in the allosteric site of the plasmodium cysteine protease falcipain-2. Antibacterial and antifungal activities were determined using the broth dilution method. ResultsS6 (N-(2-thiazol-4yl)-acetyl-aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide and S9 (N-(1H-benzo[d]imidazol-2-yl)aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide formed five hydrogen bonds; S8 (N-(2-1H-imidazol-2yl)aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide and S10 (N-(1H-benzo[d]imidazol-5-yl)aminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide formed four hydrogen bonds with the allosteric site of the enzyme. Considering the docking scores and formation of hydrogen bonds with the target enzyme, the novel derivatives were processed for wet lab synthesis. All the newly synthesized derivatives were subjected to in vitro antimalarial, antifungal, and antibacterial activities. All the derivatives exhibited sufficient sensitivity to the Plasmodium falciparum strain compared to the standards. Moreover, compounds S9 and S10 showed the most potent dual antimicrobial and antimalarial activities. They also exhibited powerful molecular interactions in molecular docking studies. ConclusionBased on the above results, it was concluded that N-(2-arylaminophenyl)-2,3-diphenylquinoxaline-6-sulfonamide derivatives have excellent biological potential to act as antimalarial, antifungal, and antibacterial agents.

Structure-aided optimization of non-nucleoside M.tuberculosis thymidylate kinase inhibitors.

Mycobacterium tuberculosis thymidylate kinase (MtTMPK) has emerged as an attractive target for rational drug design. We recently investigated new families of non-nucleoside MtTMPK inhibitors in an effort to diversify MtTMPK inhibitor chemical space. We here report a new series of MtTMPK inhibitors by combining the Topliss scheme with rational drug design approaches, fueled by two co-crystal structures of MtTMPK in complex with developed inhibitors. These efforts furnished the most potent MtTMPK inhibitors in our assay, with two analogues displaying low micromolar MIC values against H37Rv Mtb. Prepared inhibitors address new sub-sites in the MtTMPK nucleotide binding pocket, thereby offering new insights into its druggability. We studied the role of efflux pumps as well as the impact of cell wall permeabilizers for selected compounds to potentially provide an explanation for the lack of correlation between potent enzyme inhibition and whole-cell activity.