Evaluating the Therapeutic Potential of Curcumin and Synthetic Derivatives: A Computational Approach to Anti-Obesity Treatments.

Natural compounds such as curcumin, a polyphenolic compound derived from the rhizome of turmeric, have gathered remarkable scientific interest due to their diverse metabolic benefits including anti-obesity potential. However, curcumin faces challenges stemming from its unfavorable pharmacokinetic profile. To address this issue, synthetic curcumin derivatives aimed at enhancing the biological efficacy of curcumin have previously been developed. In silico modelling techniques have gained significant recognition in screening synthetic compounds as drug candidates. Therefore, the primary objective of this study was to assess the pharmacokinetic and pharmacodynamic characteristics of three synthetic derivatives of curcumin. This evaluation was conducted in comparison to curcumin, with a specific emphasis on examining their impact on adipogenesis, inflammation, and lipid metabolism as potential therapeutic targets of obesity mechanisms. In this study, predictive toxicity screening confirmed the safety of curcumin, with the curcumin derivatives demonstrating a safe profile based on their LD50 values. The synthetic curcumin derivative 1A8 exhibited inactivity across all selected toxicity endpoints. Furthermore, these compounds were deemed viable candidate drugs as they adhered to Lipinski's rules and exhibited favorable metabolic profiles. Molecular docking studies revealed that both curcumin and its synthetic derivatives exhibited favorable binding scores, whilst molecular dynamic simulations showed stable binding with peroxisome proliferator-activated receptor gamma (PPARγ), csyclooxygenase-2 (COX2), and fatty acid synthase (FAS) proteins. The binding free energy calculations indicated that curcumin displayed potential as a strong regulator of PPARγ (-60.2 ± 0.4 kcal/mol) and FAS (-37.9 ± 0.3 kcal/mol), whereas 1A8 demonstrated robust binding affinity with COX2 (-64.9 ± 0.2 kcal/mol). In conclusion, the results from this study suggest that the three synthetic curcumin derivatives have similar molecular interactions to curcumin with selected biological targets. However, in vitro and in vivo experimental studies are recommended to validate these findings.

Multi-functional pH-responsive and biomimetic chitosan-based nanoplexes for targeted delivery of ciprofloxacin against bacterial sepsis.

Bacterial sepsis is a mortal syndromic disease characterized by a complex pathophysiology that hinders effective targeted therapy. This study aimed to develop multifunctional, biomimetic and pH-responsive ciprofloxacin-loaded chitosan (CS)/sodium deoxycholic acid (SDC) nanoplexes (CS/SDC) nanoplexes with the ability to target and modulate the TLR4 pathway, activated during sepsis. The formulated nanoplexes were characterized in terms of physicochemical properties, in silico and in vitro potential biological activities. The optimal formulation showed good biocompatibility and stability with appropriate physicochemical parameters. The surface charge changed from negative at pH 7.4 to positive at pH 6.0 accompanied with a significantly faster release of CIP at pH 6.0 compared to 7.4. The biomimicry was elucidated by in silico tools and MST and results confirmed strong binding between the system and TLR4. Furthermore, the system revealed 4- and 2-fold antibacterial enhancement at acidic pH, and 3- and 4-fold better antibiofilm efficacy against Methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (P. aeruginosa) respectively, compared to bare CIP. In addition, enhanced bacterial efflux pump inhibition was demonstrated by CS/SDC nanoplexes. Finally, the developed nanosystem showed excellent antioxidant activity against DPPH radicals. Taken together, the study confirmed the multi-functionalities of CS/SDC nanoplexes and their potential benefits in improving bacterial sepsis therapy.

Dual-Target Mycobacterium tuberculosis Inhibition: Insights into the Molecular Mechanism of Antifolate Drugs.

The escalating prevalence of drug-resistant strains of Mycobacterium tuberculosis has posed a significant challenge to global efforts in combating tuberculosis. To address this issue, innovative therapeutic strategies are required that target essential biochemical pathways while minimizing the potential for resistance development. The concept of dual targeting has gained prominence in drug discovery against resistance bacteria. Dual targeting recognizes the complexity of cellular processes and disrupts more than one vital pathway, simultaneously. By inhibiting more than one essential process required for bacterial growth and survival, the chances of developing resistance are substantially reduced. A previously reported study investigated the dual-targeting potential of a series of novel compounds against the folate pathway in Mycobacterium tuberculosis. Expanding on this study, we investigated the predictive pharmacokinetic profiling and the structural mechanism of inhibition of UCP1172, UCP1175, and UCP1063 on key enzymes, dihydrofolate reductase (DHFR) and 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione 5'-phosphate reductase (RV2671), involved in the folate pathway. Our findings indicate that the compounds demonstrate lipophilic physiochemical properties that promote gastrointestinal absorption, and may also inhibit the drug-metabolizing enzyme, cytochrome P450 3A4, thus enhancing their biological half-life. Furthermore, key catalytic residues (Serine, Threonine, and Aspartate), conserved in both enzymes, were found to participate in vital molecular interactions with UCP1172, which demonstrated the most favorable free binding energies to both DHFR and RV2671 (-41.63 kcal/mol, -48.04 kcal/mol, respectively). The presence of characteristic loop shifts, which are similar in both enzymes, also indicates a common inhibitory mechanism by UCP1172. This elucidation advances the understanding of UCP1172's dual inhibition mechanism against Mycobacterium tuberculosis.

Halting aberrant DNA methylation via in silico Identification of potent inhibitors of DNMT3B enzyme: Atomistic insights.

To date, Cancer remains a global threat due to its impact on growing life expectancy. With the many efforts and methods of combating the disease, complete success remains a challenge owing to several limitations including cancer cells developing resistance through mutations, off-target effect of some cancer drugs resulting in toxicities, among many others. Aberrant DNA methylation is understood to be the primary reason for improper gene silence, which can result in neoplastic transformation, carcinogenesis, and tumour progression. DNA methyltransferase B (DNMT3B) enzyme is considered a potential target for the treatment of several cancers due to its important role in DNA methylation. However, only a few DNMT3B inhibitors have been reported to date. Herein, in silico molecular recognition techniques such as Molecular docking, Pharmacophore-based virtual screen and MD simulation were employed to identify potential inhibitors of DNMT3B that can halt aberrancy in DNA methylation. Findings initially identified 878 hit compounds based on a designed pharmacophore model from the reference compound Hypericin. Molecular docking was used to rank the hits by testing their efficiency when bound to the target enzyme and the top three (3) selected. All three (3) of the top hits showed excellent pharmacokinetic properties but two (2) (Zinc33330198 and Zinc77235130) were identified to be non-toxic. Molecular dynamic simulation of the final two hits showed good stability, flexibility, and structural rigidity of the compounds on DNMT3B. Finally, thermodynamic energy estimations show both compounds had favourable free energies comprising - 26.04 kcal/mol for Zinc77235130 and - 15.73 kcal/mol for Zinc33330198. Amongst the final two hits, Zinc77235130 showed consistency in favourable results across all the tested parameters and was thus selected as the lead compound for further experimental validation. The identification of this lead compound will form important basis for the inhibition of aberrant DNA methylation in cancer therapy.

The Unusual Architecture of RNA-Dependent RNA Polymerase (RdRp)'s Catalytic Chamber Provides a Potential Strategy for Combination Therapy against COVID-19.

The unusual and interesting architecture of the catalytic chamber of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) was recently explored using Cryogenic Electron Microscopy (Cryo-EM), which revealed the presence of two distinctive binding cavities within the catalytic chamber. In this report, first, we mapped out and fully characterized the variations between the two binding sites, BS1 and BS2, for significant differences in their amino acid architecture, size, volume, and hydrophobicity. This was followed by investigating the preferential binding of eight antiviral agents to each of the two binding sites, BS1 and BS2, to understand the fundamental factors that govern the preferential binding of each drug to each binding site. Results showed that, in general, hydrophobic drugs, such as remdesivir and sofosbuvir, bind better to both binding sites than relatively less hydrophobic drugs, such as alovudine, molnupiravir, zidovudine, favilavir, and ribavirin. However, suramin, which is a highly hydrophobic drug, unexpectedly showed overall weaker binding affinities in both binding sites when compared to other drugs. This unexpected observation may be attributed to its high binding solvation energy, which disfavors overall binding of suramin in both binding sites. On the other hand, hydrophobic drugs displayed higher binding affinities towards BS1 due to its higher hydrophobic architecture when compared to BS2, while less hydrophobic drugs did not show a significant difference in binding affinities in both binding sites. Analysis of binding energy contributions revealed that the most favorable components are the ΔEele, ΔEvdw, and ΔGgas, whereas ΔGsol was unfavorable. The ΔEele and ΔGgas for hydrophobic drugs were enough to balance the unfavorable ΔGsol, leaving the ΔEvdw to be the most determining factor of the total binding energy. The information presented in this report will provide guidelines for tailoring SARS-CoV-2 inhibitors with enhanced binding profiles.

Inside the cracked kernel: establishing the molecular basis of AMG510 and MRTX849 in destabilising KRASG12C mutant switch I and II in cancer treatment.

The Kirsten rat sarcoma oncoprotein (KRAS) has been punctuated by drug development failures for decades due to frequent mutations that occur mostly at codon 12 and the seemingly intractable targeting of the protein. However, with advances in covalent targeting, the oncoprotein is being expunged from the 'undruggable' list of proteins. This feat has seen some covalent drugs at different stages of clinical trials. The advancement of AMG510 and MRTX849 as inhibitors of cysteine mutated KRAS (KRASG12C) to phase-III clinical trials informed the biased selection of AMG510 and MRTX849 for this study. Despite this advance, the molecular and atomistic modus operandi of these drugs is yet to come to light. In this study, we employed computational tools to unravel the atomistic interactions and subsequent conformational effects of AMG510 and MRTX849 on the mutant KRASG12C. It was revealed that AMG510 and MRTX849 complexes presented similar total free binding energies, (ΔGbind), of -88.15 ± 5.96 kcal/mol and -88.71 ± 7.70 kcal/mol, respectively. Gly10, Lys16, Thr58, Gly60, Glu62, Glu63, Arg68, Asp69, Met72, His95, Tyr96, Gln99, Arg102 and Val103 interacted prominently with AMG510 and MRTX849. These residues interacted with the pharmacophoric moieties of AMG510 and MRTX849 via hydrogen bonds with decreasing bond lengths at various stages of the simulation. These interactions together with pi-pi stacking, pi-sigma and pi-alkyl interactions induced unfolding of switch I whiles compacting switch II, which could interrupt the binding of effector proteins to these interfaces. These insights present useful atomistic perspectives into the success of AMG510 and MRTX849 which could guide the design of more selective and potent KRAS inhibitors.Communicated by Ramaswamy H. Sarma.

Impact of compound mutations I1171N + F1174I and I1171N + L1198H on the structure of ALK in NSCLC pathogenesis: atomistic insights.

Anaplastic lymphoma kinase (ALK) fusion genes are found in 3%-5% of non-small cell lung cancers (NSCLCs). NSCLC is the most common type of lung cancer, accounting for 84% of all lung cancer diagnoses. Available treatment options for ALK-positive NSCLCs involve the use of ALK tyrosine kinase inhibitors (ALK-TKIs) which have shown to be effective with a high response rate. Nonetheless, the emergence of multiple compound mutations such as I1171N + F1174I or I1171N + L1198H has been reported to cause resistance to all approved ALK-TKIs. However, the underlying molecular mechanisms surrounding the impact of these compound mutants remain poorly understood. Hence, we performed molecular dynamics simulations to characterize the structural effects and functional implications of these compound mutations. Findings revealed a destabilizing effect on ALK by mutants as compared to the wild-type ALK structure. Also, further insights revealed a lower root-mean-squared fluctuation, radius of gyration, and solvent-accessible surface area values of I1171N + F1174I and I1171N + L1198H ALK compound mutations suggesting that the mutants have a more compact structure and a smaller surface area than the wild-type protein. The mutants also distorted the activation loop residues (Tyr1278, Tyr1282, and Tyr1283) in the ALK structure, which further identify them as possible disruptors of phosphorylation. In contrast to wild conformation, the mutant conformations exhibited a reduced node degree in their residue interaction networks. Collectively, our findings provide deeper insights into the deleterious effects of I1171N + F1174I and I1171N + L1198H ALK compound mutations, which may contribute to NSCLC pathogenesis.Communicated by Ramaswamy H. Sarma.

Molecular modelling of SdiA protein by selected flavonoid and terpenes compounds to attenuate virulence in Klebsiella pneumoniae.

Klebsiella pneumoniae is one of the perturbing multidrug resistant (MDR) and ESKAPE pathogens contributing to the mounting morbidity, mortality and extended rate of hospitalization. Its virulence, often regulated by quorum sensing (QS) reinforces the need to explore alternative and prospective antivirulence agents, relatively from plants secondary metabolites. Computer aided drug discovery using molecular modelling techniques offers advantage to investigate prospective drugs to combat MDR pathogens. Thus, this study employed virtual screening of selected terpenes and flavonoids from medicinal plants to interrupt the QS associated SdiA protein in K. pneumoniae to attenuate its virulence. 4LFU was used as a template to model the structure of SdiA. ProCheck, Verify3D, Ramachandran plot scores, and ProSA-Web all attested to the model's good quality. Since SdiA protein in K. pneumoniae leads to the expression of virulence, 31 prospective bioactive compounds were docked for antagonistic potential. The stability of the protein-ligand complex, atomic motions and inter-atomic interactions were further investigated through molecular dynamics simulations (MDS) at 100 ns production runs. The binding free energy was estimated using the molecular mechanics/poisson-boltzmann surface area (MM/PB-SA). Furthermore, the drug-likeness properties of the studied compounds were validated. Docking studies showed phytol possesses the highest binding affinity (-9.205 kcal/mol) while glycitein had -9.752 kcal/mol highest docking score. The MDS of the protein in complex with the best-docked compounds revealed phytol with the highest binding energy of -44.2625 kcal/mol, a low root-mean-square deviation (RMSD) value of 1.54 Å and root-mean-square fluctuation (RMSF) score of 1.78 Å. Analysis of the drug-likeness properties prediction and bioavailability of these compounds revealed their conformed activity to lipinski's rules with bioavailability scores of 0.55 F. The studied terpenes and flavonoids compounds effectively thwart SdiA protein, therefore regulate inter- or intra cellular communication and associated in virulence Enterobacteriaceae, serving as prospective antivirulence drugs.Communicated by Ramaswamy H. Sarma.

Prioritizing the Catalytic Gatekeepers through Pan- Inhibitory Mechanism of Entrectinib against ALK, ROS1 and TRKA Tyrosine Kinases.

Despite the remarkable clinical activity of kinase inhibitors against anaplastic lymphoma kinase (ALK) and the closely related Ros1 and TRKA kinases, the emergence of resistance to these inhibitors often leads to relapse in most patients. Resistance is usually in the form of mutations and brain metastasis or inhibitors failing to penetrate the blood-brain barrier. The discovery of entrectinib has recently paved way for further exploration of kinase inhibitors that target ALK after it has reportedly demonstrated potency against ALK, Ros1, and TRKA kinases. However, the molecular mechanism surrounding its multi-targeting activity remains unresolved. As such, in this study, we investigate the pan-inhibitory mechanism of entrectinib towards ALK, Ros1, and TRKA, using in silico techniques. Findings show strong binding affinities of ALK = -40.92 kcal/mol, Ros1 = -36.60 kcal/mol, and TRKA = -45.99 kcal/mol for entrectinib towards ALK, Ros1, and TRKA, respectively. Pan-inhibitory binding of entrectinib is characterized by close interaction with peculiar gatekeeper residues on each tyrosine kinase. Entrectinib induced structural stability and rigidity in the backbone conformation of all three tyrosine kinases by showing a consistent pattern of structural alterations. These structural insights provided presents a baseline for the understanding of the pan-inhibitory activity of entrectinib. Establishing the cruciality of the interactions between the phenyl ring and gatekeeper residues could guide the structure-based design of novel tyrosine kinase inhibitors with improved therapeutic activities.

Dual-Inhibition of Human N-Myristoyltransferase Subtypes Halts Common Cold Pathogenesis: Atomistic Perspectives from the Case of IMP-1088.

The pharmacological inhibition of human N-myristoyltransferase (HsNMT) has emerged as an efficient strategy to completely prevent the replication process of rhinoviruses, a potential treatment for the common cold. This was corroborated by the recent discovery of compound IMP-1088, a novel inhibitor that demonstrated a dual-inhibitory activity against the two HsNMT subtypes 1 and 2 without inducing cytotoxicity. However, the molecular and structural basis for the dual-inhibitory potential of IMP-1088 has not been investigated. As such, we employ molecular modelling techniques to resolve the structural mechanisms that account for the dual-inhibitory prowess of IMP-1088. Sequence and nanosecond-based analyses identified Tyr296, Phe190, Tyr420, Leu453, Gln496, Val181, Leu474, Glu182, and Asn246 as residues common within the binding pockets of both HsNMT1 and HsNMT2 subtypes whose consistent interactions with IMP-1088 underpin the basis for its dual inhibitory potency. Nano-second-based assessment of interaction dynamics revealed that Tyr296 consistently elicited high-affinity π-π stacked interaction with IMP-1088, thus further highlighting its cruciality corroborating previous report. An exploration of resulting structural changes upon IMP-1088 binding further revealed a characteristic impeding of residue fluctuations, structural compactness, and a consequential burial of crucial hydrophobic residues, features required for HsNMT1/2 functionality. Findings present essential structural perspectives that augment previous experimental efforts and could also advance drug development for treating respiratory tract infections, especially those mediated by rhinoviruses.

Integrating Bioinformatics Strategies in Cancer Immunotherapy: Current and Future Perspectives.

For the past few decades, the mechanisms of immune responses to cancer have been exploited extensively and significant attention has been given into utilizing the therapeutic potential of the immune system. Cancer immunotherapy has been established as a promising innovative treatment for many forms of cancer. Immunotherapy has gained its prominence through various strategies, including cancer vaccines, monoclonal antibodies (mAbs), adoptive T cell cancer therapy, and immune checkpoint therapy. However, the full potential of cancer immunotherapy is yet to be attained. Recent studies have identified the use of bioinformatics tools as a viable option to help transform the treatment paradigm of several tumors by providing a therapeutically efficient method of cataloging, predicting and selecting immunotherapeutic targets, which are known bottlenecks in the application of immunotherapy. Herein, we gave an insightful overview of the types of immunotherapy techniques used currently, their mechanisms of action, and discussed some bioinformatics tools and databases applied in the immunotherapy of cancer. This review also provides some future perspectives in the use of bioinformatics tools for immunotherapy.

The Dual-Targeting Activity of the Metabolite Substrate of Para-amino Salicyclic Acid in the Mycobacterial Folate Pathway: Atomistic and Structural Perspectives.

Therapeutic targeting of folate biosynthetic pathway has recently been explored as a viable strategy in the treatment of tuberculosis. The bioactive metabolite substrate of Para-amino salicyclic acid (PAS-M) reportedly dual-targets dihydrofolate reductase (DHFR) and flavin-dependent thymidylate synthase (FDTS), two essential enzymes in folate biosynthetic pathway. However, the molecular mechanisms and structural dynamics of this dual inhibitory activity of the PAS-M remain elusive. Molecular dynamics simulations revealed that binding of PAS-M towards DHFR is characterized by a recurrence of strong conventional hydrogen bond interactions between a peculiar DHFR binding site residue (Asp27) and the 2-amino-decahydropteridin-4-ol group of PAS-M. Similarly, the binding of PAS-M towards FDTS also involved consistent strong conventional hydrogen bond interactions between some specific residues (Tyr101, Arg172, Thr4, Gln103, Arg87 and Gln106) and, the 2-amino-decahydropteridin-4-ol group, thus establishing the cruciality of the group. Structural dynamics of the bound complexes of both enzymes revealed that, upon binding, PAS-M is anchored at the entrance of hydrophobic pockets by strong hydrogen bond interactions while the rest of the structure gains access to deeper hydrophobic residues to engage in favorable interactions. Further analysis of atomistic changes of both enzymes showed increased C-α atom deviations as well as an increase C-α atoms radius of gyration consistent with structural disorientations. These conformational changes possibly interfered with the biological functions of the enzymes and hence their inhibition as experimentally reported. Structural Insights provided could open up a novel paradigm of structure-based design of multi-targeting inhibitors of biological targets in the folate biosynthetic pathway toward tuberculosis therapy.

Triple Mycobacterial ATP-synthase mutations impedes Bedaquiline binding: Atomistic and structural perspectives.

Bedaquiline (BDQ) has demonstrated formidable bactericidal activity towards Mycobacterium tuberculosis (Mtb) in the treatment of multi-drug resistant (MDR) and extensively drug resistant (XDR) tuberculosis (TB). BDQ elicits its therapeutic function by halting the ionic shuttle of Mtb via mycobacterial F1F0 ATP-synthase blockade. However, triple mutations (L59 V, E61D and I66 M) at the ligand-binding cavity characterize emerging BDQ-resistant strains thereby restraining the potentials embedded in this anti-microbial compound, particularly in MDR/XDR-TB therapy. In this report, the effects of these triple mutations on BDQ-Mtb F1F0 ATP-synthase binding were investigated using molecular dynamics, free energy binding and residue interaction network (RIN) analyses. The highlight of our findings is the drastic reduction in BDQ binding affinity (ΔG) in the triple mutant protein, which was caused by a systemic loss in high-affinity interactions primarily mediated by L59, E61 and I66. While wildtype L59 and I66 formed pi-alkyl interactions with BDQ at the F1F0 ATP-synthase binding site, E61 elicited conventional (O--HO) bond. Upon transition, V59 and I66 were devoid of interactions with BDQ while D61 existed in a weaker non-conventional (C--HO) bond. Likewise, these mutations distorted the binding site and overall structural architecture of F1F0 ATP-synthase in the presence of BDQ as revealed by the RIN and conformational analyses. Insights from this study could serve as a starting point for the structure-based design of novel inhibitors that could overcome mutational setbacks posed by BDQ-resistant strains in MDR/XDR-TB treatment.

CF3 -Pyridinyl Substitution on Antimalarial Therapeutics: Probing Differential Ligand Binding and Dynamical Inhibitory Effects of a Novel Triazolopyrimidine-Based Inhibitor on Plasmodium falciparum Dihydroorotate Dehydrogenase.

The quest for reliable dihydroorotate dehydrogenase (DHODH) inhibitors has engendered the discovery of potential therapeutic compounds at different stages of clinical trials. Although promising, high attrition rates and unfavorable bioactivities have limited their drug developmental progress. A recent structural modification of DSM265, a triazolopyrimidine-based inhibitor, yielded DSM421, derived by the substitution of the SF5 -aniline group on DSM265 with a CF3 -pyridinyl moiety. Consequently, DSM421 exhibited improved pharmacological and pharmacokinetics attributes relative to DSM265. The improved bioactivity mediated by the CF3 -pyridinyl group leaves us with a curiosity to investigate underlying ligand-binding mechanisms and dynamics using computational methods. Presented in this study are insights that clearly explain the effects of structural SF5 -aniline→CF3 -pyridinyl modifications on pfDHODH inhibition. Findings showed that the CF3 -pyridinyl group induced an optimal and stabilized positioning of DSM421 within the binding pocket, allowing for steady and strong intermolecular interactions which favored its stronger binding affinity as estimated and correlated with bioactivity data. These interactions consequently induced a pronounced stabilization of the structural conformation of pfDHODH by restricting residue motions, which possibly underpinned its enhanced inhibitory activity relative to DSM265. Active site interactions of the CF3 -pyrinidyl group with residues Ser236, Ile237, and Phe188 characterized by strong π-π stacking and halogen interactions also stabilized its positioning which altogether accounted for its enhanced inhibitory prowess towards pfDHODH. On the contrary, fewer and weaker interactions characterized DSM265 binding which could explain its relatively lower binding affinity. Findings will facilitate the design of novel pfDHODH inhibitors with enhanced properties.

Deciphering the canonical blockade of activated Hageman factor (FXIIa) by benzamidine in the coagulation cascade: A thorough dynamical perspective.

The experimental inhibitory potency of benzamidine (BEN) paved way for further design and development of inhibitors that target ß-FXIIa. Structural dynamics of the loops and catalytic residues that encompass the binding pocket of ß-FXIIa and all serine proteases are crucial to their overall activity. Employing molecular dynamics and post-MD analysis, this study sorts to unravel the structural and molecular events that accompany the inhibitory activity of BEN on human ß-FXIIa upon selective non-covalent binding. Analysis of conformational dynamics of crucial loops revealed prominent alterations of the original conformational posture of FXIIa, evidenced by increased flexibility, decreased compactness, and an increased exposure to solvent upon binding of BEN, which could have in turn interfered with the essential roles of these loops in enhancing their procoagulation interactions with biological substrates and cofactors, altogether resulting in the consequential inactivation of FXIIa. A sustained interaction of the catalytic triad residues and key residues of the autolysis loop impeded their roles in catalysis which equally enhanced the inhibitory potency of BEN toward ß-FXIIa evidenced by a favorable binding. Findings provide essential structural and molecular insights that could facilitate the structure-based design of novel antithrombotic compounds with enhanced inhibitory activities and low therapeutic risk.

Halting ionic shuttle to disrupt the synthetic machinery-Structural and molecular insights into the inhibitory roles of Bedaquiline towards Mycobacterium tuberculosis ATP synthase in the treatment of tuberculosis.

Therapeutic targeting of the adenosine triphosphate (ATP) machinery of Mycobacterium tuberculosis (Mtb) has recently presented a potent and alternative measure to halt the pathogenesis of tuberculosis. This has been potentiated by the development of bedaquiline (BDQ), a novel small molecule inhibitor that selectively inhibits mycobacterial F1 Fo -ATP synthase by targeting its rotor c-ring, resulting in the disruption of ATP synthesis and consequential cell death. Although the structural resolution of the mycobacterial C9 ring in co`mplex with BDQ provided the first-hand detail of BDQ interaction at the c-ring region of the ATP synthase, there still remains a need to obtain essential and dynamic insights into the mechanistic activity of this drug molecule towards crucial survival machinery of Mtb. As such, for the first time, we report an atomistic model to describe the structural dynamics that explicate the experimentally reported antagonistic features of BDQ in halting ion shuttling by the mycobacterial c-ring, using molecular dynamics simulation and the Molecular Mechanics/Poisson-Boltzmann Surface Area methods. Results showed that BDQ exhibited a considerably high ΔG while it specifically maintained high-affinity interactions with Glu65B and Asp32B , blocking their crucial roles in proton binding and shuttling, which is required for ATP synthesis. Moreover, the bulky nature of BDQ induced a rigid and compact conformation of the rotor c-ring, which impedes the essential rotatory motion that drives ion exchange and shuttling. In addition, the binding affinity of a BDQ molecule was considerably increased by the complementary binding of another BDQ molecule, which indicates that an increase in BDQ molecule enhances inhibitory potency against Mtb ATP synthase. Taken together, findings provide atomistic perspectives into the inhibitory mechanisms of BDQ coupled with insights that could enhance the structure-based design of novel ATP synthase inhibitors towards the treatment of tuberculosis.