Inherent efficacies of pyrazole-based derivatives for cancer therapy: the interface between experiment and in silico.

There has been an increasing trend in the design of novel pyrazole derivatives for desired biological applications. For a cost-effective strategy, scientists have implemented various computational drug design tools to go hand in hand with experiments for the design and discovery of potentially effective pyrazole-based therapeutics. This review highlights the milestones of pyrazole-containing inhibitors and the use of molecular modeling techniques in conjunction with experimental studies to provide a view of the binding mechanism of these compounds. The review focuses on the established targets that play a key role in cancer therapy, including proteins involved in tubulin polymerization, carbonic anhydrase and tyrosine kinase. Overall, using both experimental and computational methods in drug design represents a promising approach to cancer therapy.

An In Silico Functional Analysis of Non-Synonymous Single-Nucleotide Polymorphisms of Bovine CMAH Gene and Potential Implication in Pathogenesis.

The sugar molecule N-glycolylneuraminic acid (Neu5Gc) is one of the most common sialic acids discovered in mammals. Cytidine monophospho-N-acetylneuraminic acid hydroxylase (CMAH) catalyses the conversion of N-acetylneuraminic acid (Neu5Ac) to Neu5Gc, and it is encoded by the CMAH gene. On the one hand, food metabolic incorporation of Neu5Gc has been linked to specific human diseases. On the other hand, Neu5Gc has been shown to be highly preferred by some pathogens linked to certain bovine diseases. We used various computational techniques to perform an in silico functional analysis of five non-synonymous single-nucleotide polymorphisms (nsSNPs) of the bovine CMAH (bCMAH) gene identified from the 1000 Bull Genomes sequence data. The c.1271C>T (P424L) nsSNP was predicted to be pathogenic based on the consensus result from different computational tools. The nsSNP was also predicted to be critical based on sequence conservation, stability, and post-translational modification site analysis. According to the molecular dynamic simulation and stability analysis, all variations promoted stability of the bCMAH protein, but mutation A210S significantly promoted CMAH stability. In conclusion, c.1271C>T (P424L) is expected to be the most harmful nsSNP among the five detected nsSNPs based on the overall studies. This research could pave the way for more research associating pathogenic nsSNPs in the bCMAH gene with diseases.

Uganda Genome Resource: A rich research database for genomic studies of communicable and non-communicable diseases in Africa.

The Uganda Genome Resource (UGR) is a well-characterized genomic database with a range of phenotypic communicable and non-communicable diseases and risk factors generated from the Uganda General Population Cohort (GPC), a population-based open cohort established in 1989. The UGR comprises genotype data on ∼5,000 and whole-genome sequence data on ∼2,000 Ugandan GPC individuals from 10 ethno-linguistic groups. Leveraging other platforms at MRC/UVRI and LSHTM Uganda Research Unit, there is opportunity for additional sample collection to expand the UGR to advance scientific discoveries. Here, we describe UGR and highlight how it is providing opportunities for discovery of novel disease susceptibility genetic loci, refining association signals at new and existing loci, developing and testing polygenic scores to determine disease risk, assessing causal relations in diseases, and developing capacity for genomics research in Africa. The UGR has the potential to develop to a comparable level of European and Asian large-scale genomic initiatives.

Transferability of genetic risk scores in African populations.

The poor transferability of genetic risk scores (GRSs) derived from European ancestry data in diverse populations is a cause of concern. We set out to evaluate whether GRSs derived from data of African American individuals and multiancestry data perform better in sub-Saharan Africa (SSA) compared to European ancestry-derived scores. Using summary statistics from the Million Veteran Program (MVP), we showed that GRSs derived from data of African American individuals enhance polygenic prediction of lipid traits in SSA compared to European and multiancestry scores. However, our GRS prediction varied greatly within SSA between the South African Zulu (low-density lipoprotein cholesterol (LDL-C), R2 = 8.14%) and Ugandan cohorts (LDL-C, R2 = 0.026%). We postulate that differences in the genetic and environmental factors between these population groups might lead to the poor transferability of GRSs within SSA. More effort is required to optimize polygenic prediction in Africa.

From a Computational Perspective: Elucidating the Neurotherapeutic and Inhibitory properties of LRRK2 Kinase Domain by a benzothiazole-based compound.

BACKGROUND: Parkinson's disease (PD) is one of the most prominent neurodegenerative diseases hence the continual search for viable and effective treatment options. The pathogeny of PD is driven by many key proteins among which is the recently identified Leucine-rich repeated kinase 2 (LRRK2). Going forward, the onus lies on identifying small-molecule inhibitors that can halt its pathogenic involvement, and, importantly, possess the capacity to cross the blood-brain barrier (BBB). Although several compounds have been identified over the past decade for their potencies, a major limitation remains the inability of the majority to cross the blood-brain barrier (BBB). A novel series of benzothiazole-based compounds with varying LRRK2 inhibitory activities were recently synthesized, with one compound 14 (CPD14) that notably inhibited LRRK2 and promoted neuronal progenitor proliferation. METHODS: Here, we implemented molecular modelling and computational simulation methods to characterize CPD14 inhibitory mechanisms and dynamics against LRRK2. More so, we employed pharmacokinetic parameters to evaluate the biological activity and CNS-suitability of CPD14. RESULTS: Molecular dynamics evaluation revealed that CPD14 elicited disruptive effects on the secondary structure of LRRK2, including its catalytic kinase domain. Interaction analyses at the binding site further revealed crucial residues for the affinity binding and stability of CPD14, further supported by a highly favorable binding energy (ΔG). Pharmacokinetic predictions revealed the CNS-suitability of CPD14 based on its adherence to Lipinski's rule of 5 for neurogenic compounds. Also, CPD14 exhibited inhibitory tendencies against transcription proteins such as signal transducer and activation transcription (STAT) protein and STAT3; complementary mechanisms that could account for its in vitro potency. CONCLUSION: These findings, taken together, will aid the pharmacological and pharmacokinetic optimization of novel LRRK2 inhibitors for the treatment of PD.

Piecing the Fragments Together: Dynamical Insights into the Enhancement of BRD4-BD1 (BET Protein) Druggability in Cancer Chemotherapy Using Novel 8-methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one Derivatives.

BACKGROUND: Fragment-based drug discovery in recent times has been explored in the design of highly potent therapeutics. METHODS: In this study, we explored the inhibitory dynamics of Compound 38 (Cpd38), a newly synthesized Bromodomain-containing protein 4 bromodomain 1 (BRD4-BD1) protein inhibitor derived from the synthetic coupling of Fragment 47 (Fgt47) into ABBV-075 scaffold. Using dynamic simulation methods, we unraveled the augmentative effects of chemical fragmentation on improved BRD4- BD1 inhibition. RESULTS: Findings from this study revealed that although Fgt47 exhibited a considerable ΔGbind, its incorporation into the difluoro-phenoxy pyridine scaffold (Cpd38) notably enhanced the binding affinity. Time-based analyses of interaction dynamics further revealed that the bulkiness of Cpd38 favored its interaction at the BRD4-BD1 active site relative to the fragment. Strikingly, compared to Fgt47, Cpd38 demonstrated high mobility, which could have enabled it to bind optimally and complementarily with key residues of the active site such as Ile146, Asn140, Cys136, Tyr98, Leu94, Val87, Phe83, and Trp81. DISCUSSION: On the contrary, the majority of these interactions were gradually lost in Fgt47, which could further indicate the essence of coupling it with the difluoro-phenoxy pyridine scaffold. Furthermore, Cpd38 had a more altering effect on BRD4-BDI relative to Fgt47, which could also be a result of its higher inhibitory activity. CONCLUSION: Conclusively, the design of highly potent therapeutics could be facilitated by the incorporation of pharmacologically active small molecule fragments into the scaffold of existing drugs.

Weak spots inhibition in the Mycobacterium tuberculosis antigen 85C target for antitubercular drug design through selective irreversible covalent inhibitor-SER124.

Mycobacterium tuberculosis (Mtb) encoded secreted antigen 85 enzymes (Ag85A/Ag85B/Ag85C) play that critical roles in the virulence, survival and drug-resistant TB of the pathogen. Ag85 proteins are potential antitubercular drug targets because they are essential in the catalytic synthesis of trehalose moieties and mycolic acid attachment to the Mtb cell wall. Recently, experimental protocols led to the discovery of a selective covalent Ag85 inhibitor, ß-isomer monocyclic enolphosphorus Cycliphostin (CyC8ß) compound, which targets the Ag85 serine 124 to exhibit a promising therapeutic activity. For the first time, our study unravelled the structural features among Mtb Ag85C homologs and motions and dynamics of Ag85C when the CyC8ß bound covalently and in open model conformations to the protein using bioinformatics tools and integrated Molecular dynamics simulations. Comparative Ag85C sequence analysis revealed conserved regions; 70% active site, 90% Adeniyi loop L1 and 50% loop L2, which acts as a switch between open and closed conformations. The average C-α atoms RMSD (2.05 Å) and RMSF (0.9 Å) revealed instability and high induced flexibility in the CyC8ß covalent-bound compared to the apo and open model systems, which displayed more stability and lower fluctuations. DSSP showed structural transitions of α-helices to bend and loops to 310-helices in the bound systems. SASA of CyC8ß covalent bound showed active site hydrophobic residues exposure to huge solvent. Therefore, these findings present the potential opportunity hotspots in Ag85C protein that would aid the structure-based design of novel chemical entities capable of resulting in potent antitubercular drugs.Communicated by Ramaswamy H. Sarma.

Probing Protein-protein Interactions and Druggable Site Identification: Mechanistic Binding Events Between Ubiquitin and Zinc Finger with UFM1-specific Peptidase Domain Protein (ZUFSP).

BACKGROUND: Deubiquitinating enzymes (DUBs) protein family have been implicated in some deregulated pathways involved in carcinogeneses, such as cell cycle, gene expression, and DNA damage response (DDR). Zinc finger with UFM1-specific peptidase domain protein (ZUFSP) is one of the recently discovered members of the DUBs. OBJECTIVES: To identify and cross-validate the ZUFSP binding site using the bioinformatic tools, including SiteMap&Metapocket, respectively. To understand the molecular basis of complementary ZUFSP-Ub interaction and associated structural events using MD Simulation. METHODS: In this study, four binding pockets were predicted, characterized, and cross-validated based on physiochemical features such as site score, druggability score, site volume, and site size. Also, a molecular dynamics simulation technique was employed to determine the impact of ubiquitin-binding on ZUFSP. RESULTS: Site 1 with a site score 1.065, Size 102, D scores 1.00, and size volume 261 was predicted to be the most druggable site. Structural studies revealed that upon ubiquitin-binding, the motional movement of ZUFSP was reduced when compared to the unbound ZUFSP. Also, the ZUFSP helical arm (ZHA) domain orient in such a way that it moves closer to the Ub; this orientation enables the formation of a UBD which is very peculiar to ZUFSP. CONCLUSION: The impact of ubiquitin on ZUFSP movement and the characterization of its predicted druggable site can be targeted in the development of therapeutics.

Atomistic insights into the selective therapeutic activity of 6-(2,4-difluorophenoxy)-5-((ethylmethyl)pyridine-3-yl)-8-methylpyrrolo[1,2-a]pyrazin-1(2H)-one towards bromodomain-containing proteins.

Cross-target effect has been one of the major mechanisms of drug toxicity, this has necessitated the design of inhibitors that are specifically tailored to target particular biomolecules. 6-(2,4-difluorophenoxy)-5-((ethylmethyl)pyridine-3-yl)-8-methylpyrrolo[1,2-a] pyrazin-1(2H)-one (Cpd38) is an inhibitor possessing high inhibition rate and tailored specificity towards bromodomain-containing protein 4 (BRD4). In this research, we used an array of computational techniques to provide insight at the atomistic level the specific targeting of BRD4 by Cpd38 relative to the binding of Cpd38 with E1A binding protein P300 (EP300); another bromodomain-containing protein (BCP). Comparatively, binding of Cpd38 improved the conformational stability and compactness of BRD4 protein when compared to the Cpd38 bound EP300. Also, Cpd38 induced a conformational change in the active site of BRD4 that facilitated a complementary pose between Cpd38 and BRD4 suitable for effective atomistic interactions. Expectedly, thermodynamic calculations revealed that the Cpd38-BRD4 system had higher binding energy (-36.11 Kcal/mol) than the Cpd38-EP300 system with a free binding energy of -15.86 Kcal/mol. Noteworthy is the opposing role Trp81 (acting as hydrogen bond acceptor) and Pro1074 (acting as hydrogen bond donor) found on the WPF and LPF loops respectively play in maintaining Cpd38 stability. Furthermore, the hydrogen bond acceptor/donator ratio was approximately 4:1 in Cpd38-BRD4 system compared with 2:1 in Cpd38-EP300 system. Taken together, atomistic insights and structural perspectives detailed in this report supplements the experimental report supporting the improved selectivity of Cpd38 for BRD4 ahead of other BCPs while providing leeway for the future design of BET selective agents with better pharmacological profile.

Insight into the Therapeutic Potential of a Bicyclic Hydroxypyridone Compound 2-[(2,4-Dichlorophenyl)methyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one as COMT Inhibitor in the Treatment of Parkinson's Disease: A Molecular Dynamic Simulation Approach.

Parkinson's disease (PD) is one of the most targeted neurodegenerative diseases in clinical research. Awareness of research is due to its increasing number of affected people worldwide. The pathology of PD has been linked to several key proteins upregulation such as the catechol O-Methyltransferase (COMT). Hence, the synthesis of compounds possessing inhibitory capacity has been the frontline of research in recent years. Several compounds have been synthesized among which is the nitrocatechol. However, major limitations associated with the nitrocatechol scaffold include the inability to possess adequate CNS penetration properties and hepatic toxicity associated with the compounds. However, a series of bicyclic hydroxypyridones compounds were synthesized to evaluate their inhibitory potentials on COMT protein with compound 38 (c38) 2-[(2,4-dichlorophenyl)methyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one shown to have a 40 fold increase level coverage in its IC50 over brain exposure when compared to the other synthesized compound. The molecular dynamics method was employed to understand the nature of interaction exhibited by c38. Molecular mechanics of c38 revealed a disruptive effect on the secondary structure of COMT protein. Per residue decomposition analysis revealed similar crucial residues involved in the favorable binding of c38 and tolcapone implicated its increased inhibitory capacity on COMT in preventing PD. Free binding energy (ΔGbind ) of c38 further revealed the inhibitory capacity towards COMT protein in comparison to the FDA approved tolcapone. Ligand mobility analysis of both compounds showed a timewise different mobility pattern across the simulation time frame at the active site pocket of the protein connoting the different inhibitory potency exhibited by c38 and tolcapone. Findings from this study revealed optimization of c38 could facilitate the discovery of new compounds with enhanced inhibitory properties towards COMT in treating PD.

Prospecting the therapeutic edge of a novel compound (B12) over berberine in the selective targeting of Retinoid X Receptor in colon cancer.

The Retinoid X Receptor (RXR) is an attractive target in the treatment of colon cancer. Different therapeutic binders with high potency have been used to specifically target RXR. Among these compounds is a novel analogue of berberine, B12. We provided structural and molecular insights into the therapeutic activity properties of B12 relative to its parent compound, berberine, using force field estimations and thermodynamic calculations. Upon binding of B12 to RXR, the high instability elicited by RXR was markedly reduced; similar observation was seen in the berberine-bound RXR. However, our analysis revealed that B12 could have a more stabilizing effect on RXR when compared to berberine. Interestingly, the mechanistic behaviour of B12 in the active site of RXR opposed its impact on RXR protein. This disparity could be due to the bond formation and breaking elicited between B12/berberine and the active site residues. We observed that B12 and berberine could induce a disparate conformational change in regions Gly250-Asp258 located on the His-RXRα/LBD domain. Comparatively, the high agonistic and activation potential reported for B12 compared to berberine might be due to its superior binding affinity as evidenced in the thermodynamic estimations. The total affinity for B12 (-25.76 kcal/mol) was contributed by electrostatic interactions from Glu243 and Glu239. Also, Arg371, which plays a crucial role in the activity of RXR, formed a strong hydrogen bond with B12; however, a weak interaction was elicited between Arg371 and berberine. Taken together, our study has shown the RXRα activating potential of B12, and findings from this study could provide a framework in the future design of RXRα binders specifically tailored in the selective treatment of colon cancer.

Transcription-translation error: In-silico investigation of the structural and functional impact of deleterious single nucleotide polymorphisms in GULP1 gene.

Nonsynonymous single nucleotide polymorphisms (nsSNPs) are one of the most common forms of mutations known to disrupt the product of translation thereby altering the protein structure-function relationship. GULP1 (PTB domain-containing engulfment adaptor protein 1) is an evolutionarily conserved adaptor protein that has been associated with glycated hemoglobin (HbA1c) in Genome-Wide Association Studies (GWAS). In order to understand the role of GULP1 in the etiology of diabetes, it is important to study some functional nsSNPs present within the GULP1 protein. We, therefore, used a SNPinformatics approach to retrieve, classify, and determine the stability effect of some nsSNPs. Y27C, G142D, A144T, and Y149C were jointly predicted by the pathogenic-classifying tools to be disease-causing, however, only G142D, A144T, and Y149C had their structural architecture perturbed as predicted by I-MUTANT and MuPro. Interestingly, G142D and Y149C occur at positions 142 and 149 of GULP1 which coincidentally are found within the binding site of GULP1. Protein-Protein interaction analysis also revealed that GULP1 interacted with 10 proteins such as Cell division cycle 5-like protein (CDC5L), ADP-ribosylation factor 6 (ARF6), Arf-GAP with coiled-coil (ACAP1), and Multiple epidermal growth factor-like domains protein 10 (MEGF10), etc. Taken together, rs1357922096, rs1264999716, and rs128246649 could be used as genetic biomarkers for the diagnosis of diabetes. However, being a computational study, these nsSNPs require experimental validation to explore their metabolic involvement in the pathogenesis of diseases.

East to West not North-West: Structure-Based Mechanistic Resolution of 8-Hydroxyl Replacement and Resulting Effects on the Activities of Imidazole-Based Heme Oxygenase-1 Inhibitors.

Upregulation of Heme Oxygenase-1 (HO-1) has been widely implicated in cancer growth and chemoresistance. This explains the numerous drug discovery efforts aimed at mitigating its pro-carcinogenic roles till date. In a recent study, two selective azole-based HO-1 inhibitors (Cpd1 and Cpd2) were synthesized, which exhibited differential inhibitory potencies of ~200µm. Interestingly, variations in the affinities of these compounds were determined by their positioning across specific regions of the HO-1 binding domain, pin-pointing a pharmacological interrelationship that remains unresolved. Therefore, in this study, using molecular dynamics simulations and binding free energy calculations, we investigate how dynamical orientations of these compounds influence their binding affinities at the active HO-1 domain. Findings revealed favorable binding for the bromobenzene and imidazole substituents of Cpd1 at the western and eastern regions of the HO-1 active domain. The constituent hydroxyl group was coordinated by residues Asp140 and Arg136 over the simulation period. On the contrary, stable binding of the bromobenzene and imidazole substituents were negated by the optimal orientations of the benzyl substituent, which extended into the northeastern region. These were supported by the displacement of Asp140 and Arg136, crucial for hydrogen bond formation in Cpd1. Also, we observed that Cpd2 exhibited high deviations indicative of an unstable binding relative to Cpd1. This further supports the presumption that Cpd2 was systematically oriented away from the active HO-1 region, a phenomenon that was due to the optimal motions of the benzyl group at the northeastern regions. The highlight of our findings is that the benzyl substituent in Cpd2 elicited negative effects on HO-1, vis a vis, instability, displacement of crucial residues, and low binding energy when compared to Cpd1. Findings pave the way for future drug discovery efforts related to HO-1 inhibition in cancer therapy.

Update and Potential Opportunities in CBP [Cyclic Adenosine Monophosphate (cAMP) Response Element-Binding Protein (CREB)-Binding Protein] Research Using Computational Techniques.

CBP [cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB)-binding protein] is one of the most researched proteins for its therapeutic function. Several studies have identified its vast functions and interactions with other transcription factors to initiate cellular signals of survival. In cancer and other diseases such as Alzheimer's, Rubinstein-taybi syndrome, and inflammatory diseases, CBP has been implicated and hence an attractive target in drug design and development. In this review, we explore the various computational techniques that have been used in CBP research, furthermore we identified computational gaps that could be explored to facilitate the development of highly therapeutic CBP inhibitors.

Functional Analysis of Single Nucleotide Polymorphism in ZUFSP Protein and Implication in Pathogenesis.

Researches have revealed that functional non-synonymous Single Nucleotide Polymorphism (nsSNPs) present in the Zinc-finger with UFM1-Specific Peptidase domain protein (ZUFSP) may be involved in genetic instability and carcinogenesis. For the first time, we employed in-silico approach using predictive tools to identify and validate potential nsSNPs that could be pathogenic. Our result revealed that 8 nsSNPs (rs 112738382, rs 140094037, rs 201652589, rs 201847265, rs 202076827, rs 373634906, rs 375114528, rs 772591104) are pathogenic after being subjected to rigorous filtering process. The structural impact of the nsSNPs on ZUFSP structure indicated that the nsSNPs affect the stability of the protein by lowering ZUFSP protein stability. Furthermore, conservation analysis showed that rs 201652589, rs 140094037, rs 201847265, and rs 772591104 were highly conserved. Interestingly, the protein-protein affinity between ZUFSP and Ubiquitin was altered rs 201652589, rs 140094037, rs 201847265, and rs 772591104 had a binding affinity of - 0.46, - 0.83, - 1.62, and - 1.12 kcal/mol respectively. Our study has been able to identify potential nsSNPs that could be used as genetic biomarkers for some diseases arising as a result of aberration in the ZUFSP structure, however, being a predictive study, the identified nsSNPs need to be experimentally investigated.

Structural alterations in the catalytic core of hSIRT2 enzyme predict therapeutic benefits of Garcinia mangostana derivatives in Alzheimer's disease: molecular dynamics simulation study.

Recent studies have shown that inhibition of the hSIRT2 enzyme provides favorable effects in neurodegenerative diseases such as Alzheimer's disease. Prenylated xanthone phytochemicals including α-mangostin, ß-mangostin and γ-mangostin obtained from Garcinia mangostana, a well-established tropical plant, have been shown experimentally to inhibit sirtuin enzymatic activity. However, the molecular mechanism of this sirtuin inhibition has not been reported. Using comprehensive integrated computational techniques, we provide molecular and timewise dynamical insights into the structural alterations capable of facilitating therapeutically beneficial effects of these phytochemicals at the catalytic core of the hSIRT2 enzyme. Findings revealed the enhanced conformational stability and compactness of the hSIRT2 catalytic core upon binding of γ-mangostin relative to the apoenzyme and better than α-mangostin and ß-mangostin. Although thermodynamic calculations revealed favorable binding of all the phytochemicals to the hSIRT2 enzyme, the presence of only hydroxy functional groups on γ-mangostin facilitated the occurrence of additional hydrogen bonds involving Pro115, Phe119, Asn168 and His187 which are absent in α-mangostin- and ß-mangostin-bound systems. Per-residue energy contributions showed that van der Waals and more importantly electrostatic interactions are involved in catalytic core stability with Phe96, Tyr104 and Phe235 notably contributing π-π stacking, π-π T shaped and π-sigma interactions. Cumulatively, our study revealed the structural alterations leading to inhibition of hSIRT2 catalysis and findings from this study could be significantly important for the future design and development of sirtuin inhibitors in the management of Alzheimer's disease.

Leveraging on Active Site Similarities; Identification of Potential Inhibitors of Zinc-Finger and UFSP domain Protein (ZUFSP).

BACKGROUND: ZUFSP (Zinc-finger and UFSP domain protein) is a novel representative member of the recently characterized seventh class of deubiquitinating enzymes (DUBs). Due to the roles DUBs play in genetic instability, they have become a major drug target in cancer and neurodegenerative diseases. ZUFSP, being a DUB enzyme has also been implicated in genetic stability. However, no lead compound has been developed to target ZUFSP. OBJECTIVE/METHODS: Therefore, in this study, we used a combined drug repurposing, virtual screening and per-Residue Energy Decomposition (PRED) to identify ZUFSP inhibitors with therapeutic potential. 3-bromo-6-{[4-hydroxy-1-3(3-phenylbutanoyl)piperidin-4-yl]methyl}-4H,5H,6H,7H-thieno[2,3- C]pyridine-7-one (BHPTP) which is an inhibitor of USP7 was repurposed to target ZUFSP. The rationale behind this is based on the similarity of the active between USP7 and ZUFSP. RESULTS: PRED of the binding between BHPTP and ZUFSP revealed Cys223, Arg408, Met410, Asn460, and Tyr465 as the crucial residues responsible for this interaction. The pharmacophoric moieties of BHPTP responsible for this binding along with other physiochemical properties were used as a filter to retrieve potential ligands. 799 compounds were retrieved, ZINC083241427, ZINC063648749, and ZINC063648753 were selected due to the binding energy they exhibited. Cheminformatics analysis revealed that the compounds possess high membrane permeability, however, BHPTP had a low membrane permeability. Furthermore, the compounds are drug like, having obeyed Lipinski's rule of five. CONCLUSION: Taken together, findings from this study put ZINC083241427, ZINC063648749, and ZINC063648753 as potential ZUFSP inhibitor, however, more experimental validation is required to unravel the mechanism of actions of these compounds.

Therapeutic Path to Double Knockout: Investigating the Selective Dual-Inhibitory Mechanisms of Adenosine Receptors A1 and A2 by a Novel Methoxy-Substituted Benzofuran Derivative in the Treatment of Parkinson's Disease.

The dual inhibition of adenosine receptors A1 (A1 AR) and A2 (A2A AR) has been considered as an efficient strategy in the treatment of Parkinson's disease (PD). This led to the recent development of a series of methoxy-substituted benzofuran derivatives among which compound 3j exhibited dual-inhibitory potencies in the micromolar range. Therefore, in this study, we seek to resolve the mechanisms by which this novel compound elicits its selective dual targeting against A1 AR and A2A AR. Unique to the binding of 3j in both proteins, from our findings, is the ring-ring interaction elicited by A1Phe275 (→ A2Phe170) with the benzofuran ring of the compound. As observed, this π-stacking interaction contributes notably to the stability of 3j at the active sites of A1 and A2A AR. Besides, conserved active site residues in the proteins such as A1Ala170 (→ A2Ala65), A1Ile173 (→ A2Ile68), A1Val191 (→ A2Val86), A1Leu192 (→ A2Leu87), A1Ala195 (→ A2Ala90), A1Met284 (→ A2Met179), A1Tyr375 (→ A2Tyr369), A1Ile378 (→ A2Ile372), and A1His382 (→ A2His376) were commonly involved with other ring substituents which further complement the dual binding and stability of 3j. This reflects a similar interaction mechanism that involved aromatic (π) interactions. Consequentially, vdW energies contributed immensely to the dual binding of the compound, which culminated in high ΔGbinds that were homogenous in both proteins. Furthermore, 3j commonly disrupted the stable and compact conformation of A1 and A2A AR, coupled with their active sites where Cα deviations were relatively high. Ligand mobility analysis also revealed that both compounds exhibited a similar motion pattern at the active site of the proteins relative to their optimal dual binding. We believe that findings from this study with significantly aid the structure-based design of highly selective dual-inhibitors of A1 and A2A AR.

Investigating the Mechanistic Inhibitory Discrepancies of Novel Halogen and Alkyl Di-Substituted Oxadiazole-Based Dibenzo-Azepine-Dione Derivatives on Poly (ADP-Ribose) Polymerase-1.

Numerous studies have established the involvement of Poly (ADP-ribose) Polymerase-1 (PARP-1) in cancer presenting it as an important therapeutic target over recent years. Although homology among the PARP protein family makes selective targeting difficult, two compounds [d11 (0.939 µM) and d21 (0.047 µM)] with disparate inhibitory potencies against PARP-1 were recently identified. In this study, free energy calculations and molecular simulations were used to decipher underlying mechanisms of differential PARP-1 inhibition exhibited by the two compounds. The thermodynamics calculation revealed that compound d21 had a relatively higher ΔGbind than d11. High involvement of van der Waal and electrostatic effects potentiated the affinity of d21 at PARP-1 active site. More so, incorporated methyl moiety in d11 accounted for steric hindrance which, in turn, prevented complementary interactions of key site residues such as TYR889, MET890, TYR896, TYR907. Conformational studies also revealed that d21 is more stabilized for interactions in the active site compared to d11. We believe that findings from this study would provide an important avenue for the development of selective PARP-1 inhibitors.

Computational and drug target analysis of functional single nucleotide polymorphisms associated with Haemoglobin Subunit Beta (HBB) gene.

There is overwhelming evidence implicating Haemoglobin Subunit Beta (HBB) protein in the onset of beta thalassaemia. In this study for the first time, we used a combined SNP informatics and computer algorithms such as Neural network, Bayesian network, and Support Vector Machine to identify deleterious non-synonymous Single Nucleotide Polymorphisms (nsSNPs) present in the HBB gene. Our findings highlight three major mutation points (R31G, W38S, and Q128P) within the HBB gene sequence that have significant statistical and computational associations with the onset of beta thalassaemia. The dynamic simulation study revealed that R31G, W38S, and Q128P elicited high structural perturbation and instability, however, the wild type protein was considerably stable. Ten compounds with therapeutic potential against HBB were also predicted by structure-based virtual screening. Interestingly, the instability caused by the mutations was reversed upon binding to a ligand. This study has been able to predict potential deleterious mutants that can be further explored in the understanding of the pathological basis of beta thalassaemia and the design of tailored inhibitors.