Investigating Pyruvate Dehydrogenase Kinase 3 Inhibitory Potential of Myricetin Using Integrated Computational and Spectroscopic Approaches.

Protein kinases are involved in various diseases and currently represent potential targets for drug discovery. These kinases play major roles in regulating the cellular machinery and control growth, homeostasis, and cell signaling. Dysregulation of kinase expression is associated with various disorders such as cancer and neurodegeneration. Pyruvate dehydrogenase kinase 3 (PDK3) is implicated in cancer therapeutics as a potential drug target. In this current study, a molecular docking exhibited a strong binding affinity of myricetin to PDK3. Further, a 100 ns all-atom molecular dynamics (MD) simulation study provided insights into the structural dynamics and stability of the PDK3-myricetin complex, revealing the formation of a stable complex with minimal structural alterations upon ligand binding. Additionally, the actual affinity was ascertained by fluorescence binding studies, and myricetin showed appreciable binding affinity to PDK3. Further, the kinase inhibition assay suggested significant inhibition of PDK3 by myricetin, revealing an excellent inhibitory potential with an IC50 value of 3.3 µM. In conclusion, this study establishes myricetin as a potent PDK3 inhibitor that can be implicated in therapeutic targeting cancer and PDK3-associated diseases. In addition, this study underscores the efficacy of myricetin as a potential lead to drug discovery and provides valuable insights into the inhibition mechanism, enabling advancements in cancer therapeutics.

Thymoquinone, artemisinin, and thymol attenuate proliferation of lung cancer cells as Sphingosine kinase 1 inhibitors.

Sphingosine-1-phosphate (S1P) formed via catalytic actions of sphingosine kinase 1 (SphK1) behaves as a pro-survival substance and activates downstream target molecules associated with various pathologies, including initiation, inflammation, and progression of cancer. Here, we aimed to investigate the SphK1 inhibitory potentials of thymoquinone (TQ), Artemisinin (AR), and Thymol (TM) for the therapeutic management of lung cancer. We implemented docking, molecular dynamics (MD) simulations, enzyme inhibition assay, and fluorescence measurement studies to estimate binding affinity and SphK1 inhibitory potential of TQ, AR, and TM. We further investigated the anti-cancer potential of these compounds on non-small cell lung cancer (NSCLC) cell lines (H1299 and A549), followed by estimation of mitochondrial ROS, mitochondrial membrane potential depolarization, and cleavage of DNA by comet assay. Enzyme activity and fluorescence binding studies suggest that TQ, AR, and TM significantly inhibit the activity of SphK1 with IC50 values of 35.52 µM, 42.81 µM, and 53.68 µM, respectively, and have an excellent binding affinity. TQ shows cytotoxic effect and anti-proliferative potentials on H1299 and A549 with an IC50 value of 27.96 µM and 54.43 µM, respectively. Detection of mitochondrial ROS and mitochondrial membrane potential depolarization shows promising TQ-induced oxidative stress on H1299 and A549 cell lines. Comet assay shows promising TQ-induced oxidative DNA damage. In conclusion, TQ, AR, and TM act as potential inhibitors for SphK1, with a strong binding affinity. In addition, the cytotoxicity of TQ is linked to oxidative stress due to mitochondrial ROS generation. Overall, our study suggests that TQ is a promising inhibitor of SphK1 targeting lung cancer therapy.

Exploring therapeutic potential of Rutin by investigating its cyclin-dependent kinase 6 inhibitory activity and binding affinity.

Cyclin-dependent kinase 6 (CDK6) participates in numerous signalling pathways and regulates various physiological processes. Due to its unique structural features and promising therapeutic potential, CDK6 has emerged as a drug target for designing and developing small-molecule inhibitors for anti-cancer therapeutics and other CDK6-associated diseases. The current study evaluates binding affinity and the inhibitory potential of rutin for CDK6 to develop a proof of concept for rutin as a potent CDK6 inhibitor. Molecular docking and 200 ns all-atom simulations reveal that rutin binds to the active site pocket of CDK6, forming interactions with key residues of the binding pocket. In addition, the CDK6-rutin complex remains stable throughout the simulation trajectory. A high binding constant (Ka = 7.6 × 105M-1) indicates that rutin has a strong affinity for CDK6. Isothermal titration calorimetry has further validated a strong binding of rutin with CDK6 and its spontaneous nature. The kinase activity of CDK6 is significantly inhibited by rutin with an IC50 value of 3.10 µM. Our findings highlight the significant role of rutin in developing potential therapeutic molecules to manage cancer and CDK6-associated diseases via therapeutic targeting of CDK6.

Investigating the role of thymol as a promising inhibitor of pyruvate dehydrogenase kinase 3 for targeted cancer therapy.

Protein kinases have emerged as major contributors to various diseases. They are currently exploited as a potential target in drug discovery because they play crucial roles in cell signaling, growth, and regulation. Their dysregulation is associated with inflammatory disorders, cancer, and neurodegenerative diseases. Pyruvate dehydrogenase kinase 3 (PDK3) has become an attractive drug target in cancer therapeutics. In the present study, we investigated the effective role of thymol in PDK3 inhibition due to the high affinity predicted through molecular docking studies. Hence, to better understand this inhibition mechanism, we carried out a 100 ns molecular dynamics (MD) simulation to analyse the dynamics and stability of the PDK3-thymol complex. The PDK3-thymol complex was stable and energetically favourable, with many intramolecular hydrogen bond interactions in the PDK3-thymol complex. Enzyme inhibition assay showed significant inhibition of PDK3 by thymol, revealing potential inhibitory action of thymol towards PDK3 (IC50 = 2.66 µM). In summary, we established thymol as one of the potential inhibitors of PDK3, proposing promising therapeutic implications for severe diseases associated with PDK3 dysregulation. This study further advances our understanding of thymol's therapeutic capabilities and potential role in cancer treatment.

Discovering potential inhibitors of Raf proto-oncogene serine/threonine kinase 1: a virtual screening approach towards anticancer drug development.

Raf proto-oncogene serine/threonine kinase 1 (RAF1 or c-Raf) is a serine/threonine protein kinase crucial in regulating cell growth, differentiation, and survival. Any disruption or overexpression of RAF1 can result in neoplastic transformation and other disorders such as cardiomyopathy, Noonan syndrome, leopard syndrome, etc. RAF1 has been identified as a potential therapeutic target in drug development against various complex diseases, including cancer, due to its remarkable role in disease progression. Here, we carried out a multitier virtual screening study involving different in-silico approaches to discover potential inhibitors of RAF1. After applying the Lipinski rule of five, we retrieved all phytocompounds from the IMPPAT database based on their physicochemical properties. We performed a molecular docking-based virtual screening and got top hits with the best binding affinity and ligand efficiency. Then we screened out the selected hits using the PAINS filter, ADMET properties, and other druglike features. Eventually, PASS evaluation identifies two phytocompounds, Moracin C and Tectochrysin, with appreciable anti-cancerous properties. Finally, all-atom molecular dynamics simulation (MDS) followed by interaction analysis was performed on the elucidated compounds in complex with RAF1 for 200 ns to investigate their time-evolution dynamics and interaction mechanism. Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) and Dynamical Cross-Correlation Matrix (DCCM) analyses then followed these results from the simulated trajectories. According to the results, the elucidated compounds stabilize the RAF1 structure and lead to fewer conformational alterations. The results of the current study indicated that Moracin C and Tectochrysin could serve as potential inhibitors of RAF1 after required validation.Communicated by Ramaswamy H. Sarma.

Identification of mitogen-activated protein kinase 7 inhibitors from natural products: Combined virtual screening and dynamic simulation studies.

Mitogen-activated protein kinase 7 (MAPK7) is a serine/threonine protein kinase that belongs to the MAPK family and plays a vital role in various cellular processes such as cell proliferation, differentiation, gene transcription, apoptosis, metabolism, and cell survival. The elevated expression of MAPK7 has been associated with the onset and progression of multiple aggressive tumors in humans, underscoring the potential of targeting MAPK7 pathways in therapeutic research. This pursuit holds promise for the advancement of anticancer drug development by developing potential MAPK7 inhibitors. To look for potential MAPK7 inhibitors, we exploited structure-based virtual screening of natural products from the ZINC database. First, the Lipinski rule of five criteria was used to filter a large library of ~90,000 natural compounds, followed by ADMET and pan-assay interference compounds (PAINS) filters. Then, top hits were chosen based on their strong binding affinity as determined by molecular docking. Further, interaction analysis was performed to find effective and specific compounds that can precisely bind to the binding pocket of MAPK7. Consequently, two compounds, ZINC12296700 and ZINC02123081, exhibited significant binding affinity and demonstrated excellent drug-like properties. All-atom molecular dynamics simulations for 200 ns confirmed the stability of MAPK7-ZINC12296700 and MAPK7-ZINC02123081 docked complexes. According to the molecular mechanics Poisson-Boltzmann surface area investigation, the binding affinities of both complexes were considerable. Overall, the result suggests that ZINC12296700 and ZINC02123081 might be used as promising leads to develop novel MAPK7 inhibitors. Since these compounds would interfere with the kinase activity of MAPK7, therefore, may be implemented to control cell growth and proliferation in cancer after required validations.

Investigating potential of cholic acid, syringic acid, and mangiferin as cancer therapeutics through sphingosine kinase 1 inhibition.

The signaling of sphingosine kinase 1 (SphK1) and sphingosine-1-phosphate (S1P) regulates various diseases, including multiple sclerosis, atherosclerosis, rheumatoid arthritis, inflammation-related ailments, diabetes, and cancer. SphK1 is considered an attractive potential drug target and is extensively explored in cancer and other inflammatory diseases. In this study, we have investigated the inhibitory potential and binding affinity of SphK1 with cholic acid (CA), syringic acid (SA), and mangiferin (MF) using a combination of docking and molecular dynamics (MD) simulation studies followed by experimental measurements of binding affinity and enzyme inhibition assays. We observed these compounds bind to SphK1 with a significantly high affinity and eventually inhibit its kinase activity with IC50 values of 28.23 µM, 33.35 µM, and 57.2 µM for CA, SA, and MF, respectively. Further, the docking and 100 ns MD simulation studies showed that CA, SA, and MF bind with the active site residues of SphK1 with favorable energy and strong non-covalent interactions that might be accountable for inhibiting its kinase activity. Our finding indicates that CA, SA, and MF may be implicated in designing novel anti-cancer therapeutics with an improved affinity and lesser side effects by targeting SphK1.

Naringenin as a potential inhibitor of human cyclin-dependent kinase 6: Molecular and structural insights into anti-cancer therapeutics.

Cancer is one of the major causes of global deaths and needs immediate therapeutic development. So far, several strategies have been undertaken to prevent cancer, including kinase targeting by small-molecule inhibitors. Cyclin dependent kinase 6 (CDK6) plays an essential role in cancer progression and development as its overexpression is associated with tumor development and progression. The present study demonstrated that Naringenin (NAG) binds strongly to CDK6 with a binding affinity of -7.51 kcal/mol. ATPase assay of CDK6 in the presence of NAG shows that it inhibits CDK6 with an IC50 = 3.13 µM. Fluorescence and isothermal titration calorimetry studies demonstrated that NAG binds to CDK6 with the binding constant (K) values of 3.55 × 106 M-1 and 7.06 ± 2.70 × 106 M-1, respectively. The cell-based functional studies showed that NAG decreases the cell viability of human cancer cell lines, induces apoptosis, and reduces their colonization ability. Outcomes of the present in silico and in vitro studies highlighted the significance of NAG for the development of anti-cancer leads in terms of CDK6 inhibitors and provided future implications for combinatorial anti-cancer therapies.

Myricetin inhibits breast and lung cancer cells proliferation via inhibiting MARK4.

Identifying novel molecules as potential kinase inhibitors are gaining significant attention globally. The present study suggests Myricetin as a potential inhibitor of microtubule-affinity regulating kinase (MARK4), adding another molecule to the existing list of anticancer therapeutics. MARK4 regulates initial cell division steps and is a potent druggable target for various cancers. Structure-based docking with 100 ns molecular dynamics simulation depicted activity of Myricetin in the active site pocket of MARK4 and the formation of a stable complex. The fluorescence-based assay showed excellent affinity of Myricetin to MARK4 guided by static and dynamic quenching. Moreover, the assessment of enthalpy change (∆H) and entropy change (∆S) delineated electrostatic interactions as a dominant force in the MARK4-myricetin interaction. Isothermal titration calorimetric measurements revealed spontaneous binding of Myricetin with MARK4. Further, the kinase assay depicted significant inhibition of MARK4 by Myricetin with IC50 = 3.11 µM. Additionally, cell proliferation studies established that Myricetin significantly inhibited the cancer cells (MCF-7 and A549) proliferation, and inducing apoptosis. This study provides a solid rationale for developing Myricetin as a promising anticancer molecule in the MARK4 mediated malignancies.

Impact of non-synonymous mutations on the structure and function of telomeric repeat binding factor 1.

Telomeric repeat binding factor 1 (TRF1) is one of the major components of the shelterin complex. It directly binds to the telomere and controls its function by regulating the telomerase acting on it. Several variations are reported in the TRF1 gene; some are associated with variety of diseases. Here, we have studied the structural and functional significance of these variations in the TRFH domain of TRF1. We have used cutting-edge computational methods such as SIFT, PolyPhen-2, PROVEAN, Mutation Assessor, mCSM, SDM, STRUM, MAESTRO, and DUET to predict the effects of 124 mutations in the TRFH domain of TRF1. Out of 124 mutations, we have identified 12 deleterious mutations with high confidence based on their prediction. To see the impact of the finally selected mutations on the structure and stability of TRF1, all-atom molecular dynamics (MD) simulations on TRF1-Wild type (WT), L79R and P150R mutants for 200 ns were carried out. A significant conformational change in the structure of the P150R mutant was observed. Our integrated computational study provides a comprehensive understanding of structural changes in TRF1 incurred due to the mutations and subsequent function, leading to the progression of many diseases.Communicated by Ramaswamy H. Sarma.

Investigation of sphingosine kinase 1 inhibitory potential of cinchonine and colcemid targeting anticancer therapy.

Sphingosine kinase 1 (SphK1) and sphingosine-1-phosphate (S1P) signaling regulates numerous diseases such as cancer, diabetes, and inflammation-related ailments, rheumatoid arthritis, atherosclerosis, and multiple sclerosis. The importance of SphK1 in chemo-resistance has been extensively explored in breast, lung, colon, and hepatocellular carcinomas. SphK1 is considered an attractive drug target for the development of anticancer therapy. New drug molecules targeting the S1P signaling are required owing to its pleiotropic nature and association with multiple downstream targets. Here, we have investigated the binding affinity and SphK1 inhibitory potential of cinchonine and colcemid using a combined molecular docking and simulation studies followed by experimental analysis. These compounds bind to SphK1 with a significantly high affinity and subsequently inhibit kinase activity (IC50 7-9 µM). Further, MD simulation studies revealed that both cinchonine and colcemid bind to the residues at the active site pocket of SphK1 with several non-covalent interactions, which may be responsible for inhibiting its kinase activity. Besides, the binding of cinchonine and colcemid causes substantial conformational changes in the structure of SphK1. Taken together, cinchonine and colcemid may be implicated in designing potential drug molecules with improved affinity and specificity for SphK1 targeting anticancer therapy.Communicated by Ramaswamy H. Sarma.

Identification of Phytoconstituents as Potent Inhibitors of Casein Kinase-1 Alpha Using Virtual Screening and Molecular Dynamics Simulations.

Casein kinase-1 alpha (CK1α) is a multifunctional protein kinase that belongs to the serine/threonine kinases of the CK1α family. It is involved in various signaling pathways associated with chromosome segregation, cell metabolism, cell cycle progression, apoptosis, autophagy, etc. It has been known to involve in the progression of many diseases, including cancer, neurodegeneration, obesity, and behavioral disorders. The elevated expression of CK1α in diseased conditions facilitates its selective targeting for therapeutic management. Here, we have performed virtual screening of phytoconstituents from the IMPPAT database seeking potential inhibitors of CK1α. First, a cluster of compounds was retrieved based on physicochemical parameters following Lipinski's rules and PAINS filter. Further, high-affinity hits against CK1α were obtained based on their binding affinity score. Furthermore, the ADMET, PAINS, and PASS evaluation was carried out to select more potent hits. Finally, following the interaction analysis, we elucidated three phytoconstituents, Semiglabrinol, Curcusone_A, and Liriodenine, posturing considerable affinity and specificity towards the CK1α binding pocket. The result was further evaluated by molecular dynamics (MD) simulations, dynamical cross-correlation matrix (DCCM), and principal components analysis (PCA), which revealed that binding of the selected compounds, especially Semiglabrinol, stabilizes CK1α and leads to fewer conformational fluctuations. The MM-PBSA analysis suggested an appreciable binding affinity of all three compounds toward CK1α.

Xerophthalmia with secondary malabsorption syndrome in a young lady.

Delayed recognition and treatment of vitamin A deficiency (VAD) in adults leads to devastating complications. A 24-year-old woman presented with diarrhea, malaise, and shortness of breath. Her medical history included blunt abdominal trauma for which, she had bowel resection surgery and revision surgery within a year of the last surgery at the age of 8 years. She had difficulty in night vision and dry eyes. The best-corrected visual acuity was 6/18 in the BE. On slit-lamp examination in the both eyes (BE), the conjunctiva was thick, dry-looking with wrinkling, and the cornea had diffused superficial punctate keratitis and in the left eye, there was corneal xerosis of 1.5 × 1.5 mm. Tear film breakup time was 0-s in the BE. Schirmer's were 30 mm BE. The rest of the ocular examination was within normal limits. A clinical diagnosis of xerophthalmia secondary to malabsorption was made and treated with systemic vitamin A and intense lubrication. With time, ophthalmic conditions improved, but she died due to poor general wellbeing and repeated hospital-acquired infections. The infrequent presentation of VAD in adults and the unusual etiology in this patient make this case interesting, whereas its potentially devastating consequences highlight the importance of its early recognition, treatment, and regular follow up needed by both patient and physician in the community (general practitioner and ophthalmologists) for the prevention of VAD complications and poor prognosis.

Impact of Deleterious Mutations on Structure, Function and Stability of Serum/Glucocorticoid Regulated Kinase 1: A Gene to Diseases Correlation.

Serum and glucocorticoid-regulated kinase 1 (SGK1) is a Ser/Thr protein kinase involved in regulating cell survival, growth, proliferation, and migration. Its elevated expression and dysfunction are reported in breast, prostate, hepatocellular, lung adenoma, and renal carcinomas. We have analyzed the SGK1 mutations to explore their impact at the sequence and structure level by utilizing state-of-the-art computational approaches. Several pathogenic and destabilizing mutations were identified based on their impact on SGK1 and analyzed in detail. Three amino acid substitutions, K127M, T256A, and Y298A, in the kinase domain of SGK1 were identified and incorporated structurally into original coordinates of SGK1 to explore their time evolution impact using all-atom molecular dynamic (MD) simulations for 200 ns. MD results indicate substantial conformational alterations in SGK1, thus its functional loss, particularly upon T256A mutation. This study provides meaningful insights into SGK1 dysfunction upon mutation, leading to disease progression, including cancer, and neurodegeneration.

Investigating single amino acid substitutions in PIM1 kinase: A structural genomics approach.

PIM1, is a serine/threonine proto-oncogene kinase, involved in many biological functions, including cell survival, proliferation, and differentiation, thus play a key role in oncogenesis. It plays a crucial role in the onset and progression of various hematopoietic and non-hematopoietic malignancies, including acute myeloid leukemia and prostate cancer. Mutations in PIM1, especially in its kinase domain, can induce abnormal structural changes and thus alter functionalities that can lead to disease progression and other complexities. Herein, we have performed an extensive analysis of the PIM1 mutations at sequence and structure level while utilizing state-of-the-art computational approaches. Based on the impact on PIM1, numerous pathogenic and destabilizing mutations were identified and subsequently analyzed in detail. Finally, two amino acid substitutions (W109C and F147C) in the kinase domain of PIM1 were selected to explore their impact on the PIM1 structure in a time evolution manner using all-atom molecular dynamics (MD) simulations for 200 ns. MD results indicate significant conformational altercations in the structure of PIM1, especially upon F147C mutation. This study provides a significant insight into the PIM1 dysfunction upon single amino acid substitutions, which can be utilized to get insights into the molecular basis of PIM1-associated disease progression.

An Unusual Presentation of Retrobulbar Cavernous Hemangioma in a Young Woman.

A 38-year-old woman presented with sudden-onset painful lid swelling, proptosis and external ophthalmoplegia on the right side for 20 days, associated with loss of vision for nine days. On contrast-enhanced computed tomography (CECT), a retrobulbar mass was noted involving intraconal and extraconal spaces, extending up to the orbital foramina with enhancement and thickening of meninges. CT arteriography further revealed multiple feeding vessels from the maxillary artery. Embolization of feeding vessels followed by right orbital exenteration with primary reconstruction using forehead flap was done. This is an unusual case of orbital cavernous hemangioma (OCH) which emphasizes the importance of CT arteriography in specific cases of OCH, where routine neuroimaging may be inconclusive.

MAP/Microtubule Affinity Regulating Kinase 4 Inhibitory Potential of Irisin: A New Therapeutic Strategy to Combat Cancer and Alzheimer's Disease.

Irisin is a clinically significant protein playing a valuable role in regulating various diseases. Irisin attenuates synaptic and memory dysfunction, highlighting its importance in Alzheimer's disease. On the other hand, Microtubule Affinity Regulating Kinase 4 (MARK4) is associated with various cancer types, uncontrolled neuronal migrations, and disrupted microtubule dynamics. In addition, MARK4 has been explored as a potential drug target for cancer and Alzheimer's disease therapy. Here, we studied the binding and subsequent inhibition of MARK4 by irisin. Irisin binds to MARK4 with an admirable affinity (K = 0.8 × 107 M-1), subsequently inhibiting its activity (IC50 = 2.71 µm). In vitro studies were further validated by docking and simulations. Molecular docking revealed several hydrogen bonds between irisin and MARK4, including critical residues, Lys38, Val40, and Ser134. Furthermore, the molecular dynamic simulation showed that the binding of irisin resulted in enhanced stability of MARK4. This study provides a rationale to use irisin as a therapeutic agent to treat MARK4-associated diseases.

Impact of single amino acid substitution on the structure and function of TANK-binding kinase-1.

Tank-binding kinase 1 (TBK1) is a serine/threonine protein kinase involved in various signaling pathways and subsequently regulates cell proliferation, apoptosis, autophagy, antiviral and antitumor immunity. Dysfunction of TBK1 can cause many complex diseases, including autoimmunity, neurodegeneration, and cancer. This dysfunction of TBK1 may result from single amino acid substitutions and subsequent structural alterations. This study analyzed the effect of substituting amino acids on TBK1 structure, function, and subsequent disease using advanced computational methods and various tools. In the initial assessment, a total of 467 mutations were found to be deleterious. After that, in detailed structural and sequential analyses, 13 mutations were found to be pathogenic. Finally, based on the functional importance, two variants (K38D and S172A) of the TBK1 kinase domain were selected and studied in detail by utilizing all-atom molecular dynamics (MD) simulation for 200 ns. MD simulation, including correlation matrix and principal component analysis, helps to get deeper insights into the TBK1 structure at the atomic level. We observed a substantial change in variants' conformation, which may be possible for structural alteration and subsequent TBK1 dysfunction. However, substitution S172A shows a significant conformational change in TBK1 structure as compared to K38D. Thus, this study provides a structural basis to understand the effect of mutations on the kinase domain of TBK1 and its function associated with disease progression.

Structure-based investigation of MARK4 inhibitory potential of Naringenin for therapeutic management of cancer and neurodegenerative diseases.

MAP/microtubule affinity-regulating kinase 4 (MARK4) is a member of serine/threonine kinase family and considered an attractive drug target for many diseases. Screening of Indian Medicinal Plants, Phytochemistry, and Therapeutics (IMPPAT) using virtual high-throughput screening coupled with enzyme assay suggested that Naringenin (NAG) could be a potent inhibitor of MARK4. Structure-based molecular docking analysis showed that NAG binds to the critical residues found in the active site pocket of MARK4. Furthermore, molecular dynamics (MD) simulation studies for 100 ns have delineated the binding mechanism of NAG to MARK4. Results of MD simulation suggested that binding of NAG further stabilizes the structure of MARK4 by forming a stable complex. In addition, no significant conformational change in the MARK4 structure was observed. Fluorescence binding and isothermal titration calorimetric measurements revealed an excellent binding affinity of NAG to MARK4 with a binding constant (K) = 0.13 × 106 M-1 obtained from fluorescence binding studies. Further, enzyme inhibition studies showed that NAG has an admirable IC50 value of 4.11 µM for MARK4. Together, these findings suggest that NAG could be an effective MARK4 inhibitor that can potentially be used to treat cancer and neurodegenerative diseases.

Targeting ebola virus VP40 protein through novel inhibitors: exploring the structural and dynamic perspectives on molecular landscapes.

Ebola filovirus (EBOV) is one of the deadliest known infectious agents, and a cause of Western African epidemics from 2013 to 2016. The virus has infected nearly 3000 humans and almost 1900 have died. In the past few years, various small molecules have been discovered to display efficiency against EBOV and some of them have progressed towards clinical trials. Even though continuous attempts have been made to find antiEBOV therapeutics, no potential drugs are yet approved against this viral infection. The development of small antiviral inhibitors has gained tremendous attention in the attempt to overcome EVD. With this background, we seek to offer molecular insights into EBOV VP40 protein inhibition, using all atom molecular mechanics methodology and binding free energy calculations. We have selected five novel reported inhibitors against VP40 protein, namely Comp1, Comp2, Comp3, Comp4, and Comp5, and explored their binding against the same target. It was evident from the analysis that all the inhibitors displayed stability in complex with VP40 protein; however, Comp1 exhibited enhanced stability and compactness. Comp1 unveiled favorable binding, which accounted for positive correlation motions in the active site residues. Likewise, Comp1 revealed the most promising binding (ΔGbind - 40.3504 kcal/mol) as compared to the other four inhibitors, which disclosed relatively less favorable ΔGbind. The highest binding energy of Comp1 to VP40 protein can be primarily endorsed to the upsurge in van der Waals energy by ΔEvdW - 37.1609 kcal/mol and Coulomb energy by ΔEele - 52.7332 kcal/mol. Also, the hydrogen bond network is robust in Comp1-VP40 complex, with four hydrogen bonds, whilst it is less in other inhibitors. The outcomes from this report may assist in the advancement of novel VP40 inhibitors with high selectivity and potency for EVD therapeutics.