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Cancer is a disease caused by the uncontrolled, abnormal growth of cells in different anatomic sites. In 2018, it was predicted that the worldwide cancer burden would rise to 18.1 million new cases and 9.6 million deaths. Anticancer compounds, often known as chemotherapeutic medicines, have gained much interest in recent cancer research. These medicines work through various biological processes in targeting cells at various stages of the cell’s life cycle. One of the most significant roadblocks to developing anticancer drugs is that traditional chemotherapy affects normal cells and cancer cells, resulting in substantial side effects. Recently, advancements in new drug development methodologies and the prediction of the targeted interatomic and intermolecular ligand interaction sites have been beneficial. This has prompted further research into developing and discovering novel chemical species as preferred therapeutic compounds against specific cancer types. Identifying new drug molecules with high selectivity and specificity for cancer is a prerequisite in the treatment and management of the disease. The overexpression of HSP90 occurs in patients with cancer, and the HSP90 triggers unstable harmful kinase functions, which enhance carcinogenesis. Therefore, the development of potent HSP90 inhibitors with high selectivity and specificity becomes very imperative. The activities of HSP90 as chaperones and cochaperones are complex due to the conformational dynamism, and this could be one of the reasons why no HSP90 drugs have made it beyond the clinical trials. Nevertheless, HSP90 modulations appear to be preferred due to the competitive inhibition of the targeted N-terminal adenosine triphosphate pocket. This study, therefore, presents an overview of the various computational models implored in the development of HSP90 inhibitors as anticancer medicines. We hereby suggest an extensive investigation of advanced computational modelling of the three different domains of HSP90 for potent, effective inhibitor design with minimal off-target effects.

Over decades of its identification, numerous past and ongoing research has focused on β- amyloid cleaving enzyme 1 (BACE1) therapeutic roles as a target in treating Alzheimer's disease (AD). Although the initial BACE1 inhibitors at phase-3 clinical trials tremendously reduced β-amyloidassociated plaques in patients with AD, the researchers eventually discontinued the tests for lack of potency. This discontinuation has resulted in limited drug development and discovery targeted at BACE1, despite the high demand for dementia and AD therapies. It is, therefore, imperative to describe the detailed underlying biological basis of the BACE1 therapeutic option in neurological diseases. Herein, we highlight BACE1 bioactivity, genetic properties, and role in neurodegenerative therapy. We review research contributions on BACE1 exosite-binding antibody and allosteric inhibitor development as AD therapies. The review also covers BACE1 biological function, the disease-associated mechanisms, and the enzyme conditions for amyloid precursor protein site splitting. Based on the present review, we suggest further studies on anti-BACE1 exosite antibodies and BACE1 allosteric inhibitors. Non-active site inhibition might be the way forward to BACE1 therapy in Alzheimer's neurological disorder.

Enoyl-[acyl-carrier-protein] reductase (InhA) is one of the major targets for the inhibition of Mycobacterium tuberculosis (Mtb). Herein, we introduce a drug repurposing approach against Mtb-InhA: ...

The study investigated the toxicogenic effects and molecular mechanisms of Terminalia phanerophlebia on human renal cells. The methylthiazol tetrazolium (MTT) assay was used to assess the cytotoxicity of a crude leaf extract of Terminalia phanerophlebia in Hek293 cells. Luminometry was used to determine caspase activity, phosphatidylserine externalization and necrosis. The comet assay evaluated DNA fragmentation and the lactate dehydrogenase (LDH) assay was used to assess membrane integrity. Western blotting measured the expression of bcl-2-like protein 4 (Bax), inhibitors of apoptosis proteins (IAP), cleaved poly (ADP-ribose) polymerase (cPARP), p53 and nuclear factor kappa B (NF-κB) in treated Hek293 cells. A reduction in cell viability was observed with a half maximal inhibitory concentration (IC50) of 1.36 mg/ml. At this concentration, Terminalia phanerophlebia decreased initiator and executioner caspase activity. Phosphatidylserine validated apoptosis in IC25-treated cells, while necrosis was observed in all treated cells. Comet formation indicated that there was DNA fragmentation. High levels of p53 resulted in upregulation of Bax in IC25-treated cells, while the opposite was noted in IC50-treated cells. Upregulation of NF-κB is associated with decreased caspase-3 and cPARP and further supported by an increase in IAP indicating that Hek293 cell death was mainly through apoptosis and necrosis. The findings suggest that while Terminalia phanerophlebia is a good extract for tuberculosis therapeutic intervention, it may exert toxic effects on kidney cells via the apoptotic pathway.

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.

β-amyloid precursor protein cleaving enzyme1 (BACE1) has prominently been an important drug design target implicated in Alzheimer's disease pathway. The failure rate of most of the already tested drugs at different clinical phases remains a major concern. Recently, AM-6494 was reported as a novel potent, highly selective, and orally effective inhibitor against BACE1. AM-6494 displayed no alteration of skin/fur colour in animal studies, an adverse effect common to previous BACE1 inhibitors. However, the atomistic molecular mechanism of BACE1 inhibition by AM-6494 remains unclear. To elucidate the binding mechanism of AM-6494 relative to umibecestat (CNP-520) as well as the structural changes when bound to BACE1, advanced computational techniques such as accelerated MD simulation and principal component analysis have been utilised. The results demonstrated higher binding affinity of AM-6494 at BACE1 with van der Waals as dominant energy contributor compared to umibecestat. Conformational monitoring of the β-hairpin flap covering the active site revealed an effective flap closure when bound with AM-6494 compared to CNP-520, which predominantly alternates between semi-open and closed conformations. The observed effective flap closure of AM-6494 explains its higher inhibitory power towards BACE1. Besides the catalytic Asp32/228 dyad, Tyr14, Leu30, Tyr71 and Gly230 represent critical residues in the potency of these inhibitors at BACE1 binding interface. The findings highlighted in this research provide a basis to explain AM-6494 high inhibitory potency and might assist in the design of new inhibitors with improved selectivity and potency for BACE1.

In light of the rapid rise of an influenza pandemic, the constant genetic mutations of H5N1 influenza viruses pose a threat. Mutations at the sialic site are often responsible for multiple drug resistance. To design effective new inhibitors, it is necessary to undertake research into the mechanism of resistance of influenza viruses and their rapid mutations. The molecular dynamic simulation technique has been an instrumental tool in understanding how proteins function from an atomic perspective. A thorough investigation has not been conducted using molecular dynamics to examine the impact of these mutations (I222K, H274Y, and H274Y-I222K) on Peramivir. This study investigates the effects of I222K, H274Y, H274Y-I222K substitution on the neuraminidase–Peramivir complex and identifies responsible residues for complex conformations. The mutations caused distorted Peramivir orientation in the enzyme active site, which affected the inhibitor’s binding. In the presence of various mutations, interaction between protein and ligand became less thermodynamically favorable. We observed the following trend in binding free energy difference: WT

The growing occurrence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis (Mtb) strains underscores an urgent need for new antibiotics. The development of ...

The identification of dual inhibitors targeting the active sites of the cholinesterase enzymes, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), have lately surfaced as a multi-approa...

Background:β-site amyloid precursor protein cleaving enzyme (BACE 1) is the ratelimiting enzyme in the formation of neurotoxic β-amyloid (Aβ) residues (Aβ1-40 or Aβ1-42) considered as key players in the onset of Alzheimer’s Disease (AD). Consequently, BACE 1 is one of the principal targets of anti-AD therapy with many small molecule BACE 1 inhibitors (BACE 1Is) in clinical trials. AZD3293 (Lanabecestat) is a BACE 1I that concluded in phase 2/3 clinical trials. Due to the limited knowledge about the interaction of this drug with the BACE 1 enzyme, in the present study, we performed comprehensive Molecular Dynamics (MD) analysis to understand the binding mechanism of AZD3293 to BACE 1.Methods:A production run of 120 ns is carried out and results are analysed using Root Mean Square Deviation (RMSD), root mean square fluctuation (RMSF), and radius of gyration (Rg) to explain the stability of enzyme ligand complex. Further, the distance (d1) between the flap tip (Thr72) and the hinge residue of the flexible loop (Thr328), in relation to θ1 (Thr72–Asp228- Thr328), and to the dihedral angle δ (Thr72-Asp35-Asp228-Thr328) were measured.Results:The presence of the ligand within the active site restricted conformational changes as shown by decreased values of RMSF and average RMSD of atomic positions when compared to the values of the apoenzyme. Further analysis via the flap dynamics approach revealed that the AZD3293 decreases the flexibility of binding residues and made them rigid by altering the conformational changes.Conclusion:The prospective binding modes of AZD3293 from this study may extend the knowledge of the BACE 1-drug interaction and pave the way to design analogues with similar inhibitory properties needed to slow the progression of Alzheimer’s disease.

Background and purpose Tuberculosis has been reported to be the worldwide leading cause of death resulting from a sole infectious agent. The emergence of multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis has made the battle against the infection more difficult since most currently available therapeutic options are ineffective against these resistant strains. Therefore, novel molecules need to be developed to effectively treat tuberculosis disease. Preliminary docking studies revealed that tetrahydropyrimidinone derivatives have favorable interactions with the thymidylate kinase receptor. In the present investigation, we report the synthesis and the mycobacterial activity of several pyrimidinones and pyrimidinethiones as potential thymidylate kinase inhibitors. Methods The title compounds (1a-d) and (2a-b) were synthesized by a one-pot three-component Biginelli reaction. They were subsequently characterized and used for whole-cell anti-TB screening against H37Rv and multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB) by the resazurin microplate assay (REMA) plate method. Molecular modeling was conducted using the Accelry's Discovery Studio 4.0 client program to explain the observed bioactivity of the compounds. The pharmacokinetic properties of the synthesized compounds were predicted and analyzed. Results Of the compounds tested for anti-TB activity, pyrimidinone 1a and pyrimidinethione 2a displayed moderate activity against susceptible MTB H37Rv strains at 16 and 32 µg/mL, respectively. Only compound 2a was observed to exert modest activity at 128 µg/mL against MTB strains with cross-resistance to rifampicin and isoniazid. The presence of the trifluoromethyl group was essential to retain the inhibitory activity of compounds 1a and 2a. Molecular modeling studies of these compounds against thymidylate kinase targets demonstrated a positive correlation between the bioactivity and structure of the compounds. The in-silico ADME (absorption, distribution, metabolism, and excretion) prediction indicated favorable pharmacokinetic and drug-like properties for most compounds. Conclusion Pyrimidinone 1a and pyrimidinethione 2a were identified as the leading compounds and can serve as a starting point to develop novel anti-TB therapeutic agents.

CDK-1 and CDK-2 are two promising targets for cancer treatment as they are vital in tumor development, proliferation, and apoptosis during the cell cycle process. In treating cancers, CDK inhibitors (small molecules) are used to prevent the overproliferation and overexpression of cancer cells. Consequently, inhibiting CDKs is a promising treatment strategy in oncology. The limitations imposed by current CDK-1 and CDK-2 inhibitors, including neurotoxicity and the development of resistance, have prompted our group to use the novel synthesized pyrazole-thiazole hybrid analogues to investigate their possible potency against CDK-1 and CDK-2. The research study employed detailed computational approaches including molecular docking, molecular dynamics (MD) simulations, post-MD analyses such as RMSD, RMSF, RoG, per-residue energy decomposition, hydrogen bond lifetime analysis, and drug-likeness studies like ADME properties prediction and cytotoxicity, to predict the properties and inhibitory potentials of synthesized pyrazole-thiazole hybrid analogues against CDK-1 and CDK-2. The in silico binding free energy and other analysis reported in the study revealed that four (7 g, 8a, 8b, and 8 h) of the tested molecules against CDK-1 demonstrated a higher binding affinity and structural influence on the target protein than the known inhibitor, Roscovitine (RVT). Similarly, in the case of CDK-2, four (7b, 8a, 8b, and 8f) of the tested compounds showed better results than (RVT). Furthermore, structural examination of the two proteins after binding to the inhibitors revealed that the compounds form stable complexes with the targets and significantly reduced the structural flexibility of the proteins. Therefore, this study suggests the novel pyrazole-thiazole hybrid analogues as potential CDK-1 and CDK-2 inhibitors and could be potential lead compounds for target-based anticancer drugs inhibiting the important proteins, CDK-1 and CDK-2.

Berberine, an active compound in the extract of golden seal (an age-long remedy for many infections) has been confirmed to be responsible for the extract's activity against multi-drug resistant strain of Mycobacterium tuberculosis. There is no available study that shows the exact target of berberine in M tuberculosis, although it is confirmed that berberine inhibits the polymerisation of filamentous temperature-sensitive mutant Z (FtsZ), an important bacteria cytokinesis protein, in Escherichia coli, suggesting that FtsZ could as well be the target of berberine in M tuberculosis. In this study, we carried out ligand-based virtual screening to identify analogues of berberine followed by molecular dynamics (MD) simulations of the complexes of Mtb-FtsZ with berberine (berb1) and the five selected analogues (berb9 [ZINC1709414], berb37 [ZINC238749993], berb38 [ZINC13509022], berb43 [ZINC14765594], and berb48 [ZINC238758595]). Post-MD analyses such as binding free energy, RMSD, RMSF, RoG and hydrogen bond lifetime analysis were used to understand the interactions between these ligands and the receptor. The results suggested that Mtb-FtsZ could likely be the target of berberine in M tuberculosis as it forms a stable complex coupled with a significantly high binding energy. The study also identified other potential inhibitors of MTB-FtsZ polymerisation. Berb38 specifically showed greater interaction with the residues at the binding site of the protein, forming a far more stable complex with the receptor than any of the other compounds under investigation, including berberine itself. ADME properties calculations also predicted all the ligands to be bioactive as orally administered drugs.

In over a century since its discovery, Alzheimer’s disease (AD) has continued to be a global health concern due to its incurable nature and overwhelming increase among older people. In this paper, we give an overview of the efforts of researchers towards identifying potent BACE1 exosite-binding antibodies and allosteric inhibitors. Herein, we apply computer-aided drug design (CADD) methods to unravel the interactions of some proposed psychotic and meroterpenoid BACE1 allosteric site inhibitors. This study is aimed at validating the allosteric potentials of these selected compounds targeted at BACE1 inhibition. Molecular docking, molecular dynamic (MD) simulations, and post-MD analyses are carried out on these selected compounds, which have been experimentally proven to exhibit allosteric inhibition on BACE1. The SwissDock software enabled us to identify more than five druggable pockets on the BACE1 structural surface using docking. Besides the active site region, a melatonin derivative (compound 1) previously proposed as a BACE1 allostery inhibitor showed appreciable stability at eight different subsites on BACE1. Refinement with molecular dynamic (MD) simulations shows that the identified non-catalytic sites are potential allostery sites for compound 1. The allostery and binding mechanism of the selected potent inhibitors show that the smaller the molecule, the easier the attachment to several enzyme regions. This finding hereby establishes that most of these selected compounds failed to exhibit strong allosteric binding with BACE1 except for compound 1. We hereby suggest that further studies and additional identification/validation of other BACE1 allosteric compounds be done. Furthermore, this additional allosteric site investigation will help in reducing the associated challenges with designing BACE1 inhibitors while exploring the opportunities in the design of allosteric BACE1 inhibitors.

Developing new, more effective antibiotics against resistant Mycobacterium tuberculosis that inhibit its essential proteins is an appealing strategy for combating the global tuberculosis (TB) epidemic. Finding a compound that can target a particular cavity in a protein and interrupt its enzymatic activity is the crucial objective of drug design and discovery. Such a compound is then subjected to different tests, including clinical trials, to study its effectiveness against the pathogen in the host. In recent times, new techniques, which involve computational and analytical methods, enhanced the chances of drug development, as opposed to traditional drug design methods, which are laborious and time-consuming. The computational techniques in drug design have been improved with a new generation of software used to develop and optimize active compounds that can be used in future chemotherapeutic development to combat global tuberculosis resistance. This review provides an overview of the evolution of tuberculosis resistance, existing drug management, and the design of new anti-tuberculosis drugs developed based on the contributions of computational techniques. Also, we show an appraisal of available software and databases on computational drug design with an insight into the application of this software and databases in the development of anti-tubercular drugs. The review features a perspective involving machine learning, artificial intelligence, quantum computing, and CRISPR combination with available computational techniques as a prospective pathway to design new anti-tubercular drugs to combat resistant tuberculosis.

Tuberculosis (TB) remains a long-standing burdening disease to control worldwide. The lengthy current TB treatment, which boasts with unbearable adverse effects, and frequent emergence of drug resistant strains of M. tuberculosis lays an increasing burden. This behests urgent discovery and development of alternative novel medicine to alleviate TB. In this report, in silico methods were applied to examine the propensity of W. salutaris active compounds as potential inhibitors of M. tuberculosis fatty acid biosynthesis protein (FabF). Thirteen compounds were virtually screened against FabF and subjected to molecular dynamics simulations and post-dynamics analyses to examine their inhibitory potential. Betulinic acid, ursolic acid and ursolic acid acetate had the best binding energies and hence the best inhibitory potential against FabF and desirable cytotoxicity profile. These compounds bind and interact with FabF active site residues to exert their inhibitory potential. Findings in this preliminary report warrant further experimental validation towards the development of these compounds as potential drugs targeting FabF in the treatment of tuberculosis.

Drug-resistant tuberculosis (TB) infections are on the rise and anti-tuberculosis drugs that inhibit Mycobacterium tuberculosis (M. tuberculosis) through a new novel mechanism could be an important component of evolving TB therapy. Pantothenate kinase (PanK) and CTP synthetase (PyrG) are both essential for de novo pyrimidine biosynthesis. Given the extensive knowledge base on de novo pyrimidine biosynthesis inhibition of M. tuberculosis growth and survival, these enzymes present an interesting opportunity for anti-mycobacterial drug discovery. A recent experimental study shows that CDD-823953 and GSK-735826A act as dual PanK and PyrG inhibitors, respectively. However, the molecular mechanisms of their selective inhibition remain elusive. Herein, density functional theory (DFT) calculation was applied to unveil the molecular and reactivity properties of two lead compounds targeting these enzymes in a shot. Molecular dynamics simulations were then employed to investigate the inhibitory mechanism as well as selectivity impact of these potential inhibitors for their enzymes. Computational modeling of the ligands and the enzyme–ligand systems reveal that CDD-823953 and GSK-735826A lead compounds can potentially inhibit both PanK and PyrG thereby creating a pathway via the use of double target approach in tuberculosis treatment.

This study determined the susceptibility of Anopheles mosquitoes to some agricultural insecticides used in the Adansi North District of the Ashanti Region, and the efficacy of Actellic (pirimiphos-methyl) 50 EC as an alternative insecticide for the control of mosquitoes in the district. Anopheleslarvae were collected from mosquito breeding sites near farms. Five insecticides were assayed, pirimiphos-methyl (0.9%), DDT (4%), propoxur (0.1%), deltamethrin (0.05%), and lambda-cyhalothrin (0.05%). The residual efficacy of pirimiphos-methyl 50 EC sprayed on two surfaces (mud and cement) were determined by cone bioassay test at two-weekly intervals for 15 weeks after spraying. The susceptibility test showed the levels of phenotypic resistance of Anopheles spp. to the agricultural insecticides. Anopheles gambiae s.l. (96.50%) was the most dominant Anopheles species. The principal malaria vector in the district was resistant to DDT, Propoxur, Deltamethrin, and Lambda-cyhalothrin. Pirimiphos-methyl an organophosphate remained effective against the malaria vector. Student t-test analysis of bioassay test results showed that statistically the average mortality of Anopheles mosquitoes on cement surface was higher than the average mortality on mud surface. In conclusion, agricultural insecticides used in the district were negatively affecting malaria vector control activities. The use of pirimiphos-methyl (Actellic 50 EC) as an alternative insecticide against the malaria vector was more effective on cemented wall surface than on mud surface wall.

Fifteen 2-quinolone thiosemicarbazone derivatives of which eleven were new, were synthesized at room temperature. The key intermediate was the quinolone carbaldehyde, from which thiosemicar...

Carbapenem-resistant Enterobacteriaceae (CREs)-mediated infections remain a huge public health concern. CREs produce enzymes such as metallo-β-lactamases (MBLs), which inactivate β-lactam antibiotics. Hence, developing efficient molecules capable of inhibiting these enzymes remains a way forward to overcoming this phenomenon. In this study, we demonstrate that pyridyl moieties favor the inhibitory activity of cyclic metal-chelating agents through in vitro screening, molecular modeling, and docking assays. Di-(2-picolyl) amine and tris-(2-picolyl) amine exhibited great efficacy against different types of MBLs and strong binding affinity for NDM-1, whereas 2-picolyl amine did not show activity at a concentration of 64 mg/L in combination with meropenem; it further showed the lowest binding affinity from computational molecular analysis, commensurating with the in vitro screening assays. The findings revealed that the pyridyl group plays a vital role in the inhibitory activity of the tested molecules against CREs and should be exploited as potential MBL inhibitors.

Drug-resistant Mycobacterium tuberculosis poses a great threat to public health and remains one of the red-flag tagged infectious diseases, with the tendency of comorbidity with other disease conditions such as HIV/AIDS. This perhaps is responsible for redoubling of effort in tuberculosis research and continuous change in patient management to optimize the drug therapy. Aminoacyl-tRNA synthetases are essential enzymes in M. tuberculosis that catalyse the transfer of a particular amino acid to its corresponding specific tRNA to form an aminoacyl-tRNA. These enzymes are believed to be novel antibacterial, antifungal and antiparasitic drug targets because of their role in the process of protein translation. Therefore, their existence as a compliment of M. tuberculosis has attracted a lot of research interest with the aim of curbing the scourge and provide the most effective drug in the treatment of tuberculosis. This leads to the discovery of a pool of aminoacyl-tRNA synthetases with their essential inhibitors. This review seeks to articulate the current advances in the development of new TB drugs exhibiting novelty in their mode of action with specific emphasis on aminoacyl-tRNA synthetases as drug targets.

Rational modification of known drug candidates to design more potent ones using computational methods has found application in drug design, development, and discovery. Herein, we integrate computational and theoretical methodologies to unveil rivastigmine derivatives as dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) for Alzheimer's disease (AD) management. The investigation entails pharmacokinetics screening, density functional theory (DFT) mechanistic study, molecular docking, and molecular dynamics (MD) simulation. We designed over 20 rivastigmine substituents, subject them to some analyses, and identified RL2 with an appreciable blood-brain barrier score and no permeability glycoprotein binding. The compound shows higher acylation energy and a favored binding affinity to the cholinesterase enzymes. RL2 interacts with the AChE and BuChE active sites showing values of -41.1/-39.5 kcal mol -1 while rivastigmine binds with -32.7/-30.7 kcal mol -1 for these enzymes. The study revealed RL2 (4-fluorophenyl rivastigmine) as a potential dual inhibitor for AChE and BuChE towards Alzheimer's disorder management.

The escalating burden of tuberculosis disease and drastic effects of current medicine has stimulated a search for alternative drugs. A medicinal plant Warburgia salutaris has been reported to possess inhibitory properties against M. tuberculosis. In this study, we apply computational methods to investigate the probability of W. salutaris compounds as potential inhibitors of M. tuberculosis QcrB protein. We performed molecular docking, molecular dynamics simulations, radius of gyration, principal component analysis (PCA), and molecular mechanics-generalized born surface area (MM-GBSA) binding-free energy calculations in explicit solvent to achieve our objective. The results suggested that ursolic acid (UA) and ursolic acid acetate (UAA) could serve as preferred potential inhibitors of mycobacterial QcrB compared to lansoprazole sulphide (LSPZ) and telacebec (Q203)-UA and UAA have a higher binding affinity to QcrB compared to LSPZ and Q203 drugs. UA binding affinity is attributed to hydrogen bond formation with Val120, Arg364 and Arg366, and largely resonated from van der Waals forces resulting from UA interactions with hydrophobic amino acids in its vicinity. UAA binds to the porphyrin ring binding site with higher binding affinity compared to LSPZ. The binding affinity results primarily from van der Waals forces between UAA and hydrophobic residues of QcrB in the porphyrin ring binding site where UAA binds competitively. UA and UAA formed stable complexes with the protein with reduced overall residue mobility, consequently supporting the magnitude of binding affinity of the respective ligands. UAA could potentially compete with the porphyrin ring for the binding site and deprive the mycobacterial cell from oxygen, consequently disturbing mycobacterial oxygen-dependent metabolic processes. Therefore, discovery of a compound that competes with porphyrin ring for the binding site may be useful in QcrB pharmocological studies. UA proved to be a superior compound, although its estimated toxicity profile revealed UA to be hepatotoxic within acceptable parameters. Although preliminary findings of this report still warrant experimental validation, they could serve as a baseline for the development of new anti-tubercular drugs from natural resources that target QcrB.

Introduction: Alzheimer's disease (AD) is an intensifying neurodegenerative illness due to its irreversible nature. Identification of β‐site Amyloid Precursor Protein (APP) cleaving en-zyme1 (BACE1) has been a significant medicinal focus towards AD treatment, and this has opened ground for several investigations. Despite the numerous works in this direction, no BACE1 inhibitor has made it to the final approval stage as an anti-AD drug. Method: We provide an introductory background of the subject with a general overview of the pathogenesis of AD. The review features BACE1 inhibitor design and development with a focus on some clinical trials and discontinued drugs. Using the topical keywords BACE1, inhibitor design, and computational/theoretical study in the Web of Science and Scopus database, we retrieved over 49 relevant articles. The search years are from 2010 and 2020, with analysis conducted from May 2020 to March 2021. Results and Discussion: Researchers have employed computational methodologies to unravel po-tential BACE1 inhibitors with a significant outcome. The most used computer-aided approach in BACE1 inhibitor design and binding/interaction studies are pharmacophore development, quantita-tive structure-activity relationship (QSAR), virtual screening, docking, and molecular dynamics (MD) simulations. These methods, plus more advanced ones including quantum mechan-ics/molecular mechanics (QM/MM) and QM, have proven substantial in the computational frame-work for BACE1 inhibitor design. Computational chemists have embraced the incorporation of in vitro assay to provide insight into the inhibition performance of identified molecules with potential inhibition towards BACE1. Significant IC50 values up to 50 nM, better than clinical trial com-pounds, are available in the literature. Conclusion: Researchers have employed computational methodologies to unravel po-tential BACE1 inhibitors with a significant outcome. The most used computer-aided approach in BACE1 inhibitor design and binding/interaction studies are pharmacophore development, quantita-tive structure-activity relationship (QSAR), virtual screening, docking, and molecular dynamics (MD) simulations. These methods, plus more advanced ones including quantum mechan-ics/molecular mechanics (QM/MM) and QM, have proven substantial in the computational frame-work for BACE1 inhibitor design. Computational chemists have embraced the incorporation of in vitro assay to provide insight into the inhibition performance of identified molecules with potential inhibition towards BACE1. Significant IC50 values up to 50 nM, better than clinical trial com-pounds, are available in the literature.

Optimization and re-optimization of bioactive molecules using in silico methods have found application in the design of more active ones. Herein, we applied a pharmacophore modeling approach to screen potent dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) aimed at Alzheimer's disease (AD) treatment. The investigation entails molecular dynamics simulation, docking, pharmacophore modeling, drug-like screening, and binding energy analysis. We prepared a pharmacophore model from approved inhibitors of AChE and BuChE to predict the crucial moieties required for optimum molecular interaction with these proteins. The obtained pharmacophore model, used for database screening via some critical criteria, showed 229 hit molecules. Further analyses showed 42 likely dual inhibitors of AChE/BuChE with drug-like and pharmacokinetics properties the same as the approved cholinesterase inhibitors. Finally, we identified 14 dual molecules with improved potentials over the existing inhibitors and simulated ZINC92385797 bound to human AChE and BuChE structure after noticing that these 14 molecules are similar. The selected compound maintained relative stability at the active sites of both proteins over 120 ns simulation. Our integrated protocols showed the pertinent recipes of anti-AD drug design through the in silico pipeline.