BACKGROUND: Type 2 diabetes mellitus, or T2DM, is one of the world's most chronic health problems that is linked to numerous deaths and high health care expenses. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), protein-tyrosine phosphatase 1B (PTP1B) and mono-ADP-ribosyl transferase sirtuin-6 (SIRT6) were among the novel proteins and focus targets of diabetes research. Annona muricata is a commonly used natural remedy for several illnesses, including type 2 diabetes mellitus. However, most of these traditional claims have received few molecular evaluations. OBJECTIVES: This investigated the phytoconstituents and derivatives of the leaves of A. muricata by evaluating their binding profiles towards selected novel T2DM-related protein targets through in silico methods. METHODOLOGY: This study screened the potential lead compounds from the leaves of A. muricata by evaluating the binding energies of the parent compounds and derivatives with the targets compared to the native ligands and known substrates through molecular docking simulations. Additionally, pharmacokinetic, physicochemical properties, and binding interactions were also assessed using several software programs and online databases. RESULTS: Out of the 8 selected parent compounds of Annona muricata, a total of 672 derivatives were designed, tested, and compared against the controls for at least one of the three protein targets. Among these, 280 derivatives exhibited more negative binding energies than controls in each protein target. CONCLUSION The designed derivatives can be synthesized and further investigated for potential biological effects towards 11β-HSD1, PTP1B, and SIRT6 through in vitro and in vivo experiments.
Type 2 Diabetes Mellitus ; Alkaloids

Background: Malaria remains to be one of the major health problems in tropical areas of the world. It puts at least one-third of the world population at risk of infection and afflicts over 200 million people worldwide, approximately 7000 of whom are Filipinos. In spite of available drugs, malarial chemotherapy is still insufficient. The increased resistance of Plasmodium falciparum strains to existing antimalarial drugs prompts the discovery of new therapeutic agents for malaria. Objective: This study aimed to uncover, through molecular docking technique, new chemical entities that can be developed as new drugs for malaria. Methodology: In this study, 2,527 approved and 5,755 experimental drugs from DrugBank and 4,687 natural compounds from Analyticon MEGx database were docked against Plasmodium falciparum aspartate transcarbamoylase (PfATC) and oritidine-5'-monophosphate decarboxylase (PfOMPDC), two key enzyme targets involved in the de novo biosynthesis pathway of the pathogen. Results: A total of 39 compounds (1 approved drug, 19 experimental drugs, 19 natural products) had larger binding energy (BE) values than the known ligands 2,3-naphthalenediol (BE = -7.0 kcal/mol) and uridine 5- PfATC monophosphate (BEPfOMPDC = -9.0 kcal/mol). The top 3 hits were natural products: dihydrotrichotetronine (BEPfATC = -21 kcal/mol, BE = -18 kcal/mol), ginkgolide A (BE = -19 kcal/mol, BE = -15 kcal/mol), and PfOMPDC PfATC PfOMPDC ginkgolide C (BE = -16 kcal/mol, BE = -16 kcal/mol). Conclusion Based on calculated binding energy and ADMET properties, dihydrotrichotetronine, ginkgolide A, and ginkgolide C are the best natural product candidates for further development as dual inhibitors for both PfATC and PfOMPDC enzymes. Furthermore, myricetin (BE = -9 kcal/mol, BE = -10 kcal/mol) and PfATC PfOMPDC tolcapone (BE = -9.1 kcal/mol, BE = -9.2 kcal/mol) may also be repurposed as anti-malarial drugs.
Malaria

Background: The biological activity of a compound is assumed to be encoded in its chemical composition and geometric structure, from which physico-chemical, electrotopological, and graph theory-derived properties can be determined. Objective: This study aimed to identify the molecular descriptors derived from Dragon® 6 software that can discriminate compounds as drug or nondrug Methodology: Over 4000 molecular properties were obtained for approximately 2000 known drugs and 2000 nondrugs on which Linear Discriminant Analysis was performed. Results: Compounds can be discriminated between drug and nondrug with 81% accuracy using only two molecular descriptors, the information index HVcpx and the topological index MDDD. Conclusion A “Rule of Three” (HVcpx ≤ 3 and MDDD ≥ 30) seems to confer druglikeness in compounds. This rule can be used as additional filter in high throughput screening of compounds in any drug discovery research.
Discriminant Analysis ; Drug Discovery

Background: Breast cancer is one of the leading causes of deaths in women worldwide, affecting nearly 7.8 million people. In 2020 in the Philippines, there were around 150,000 Filipinos who were newly diagnosed with the disease. The complex pathogenesis of breast cancer in addition to the emergence of resistance to therapy makes the treatment very challenging. Compounds that can antagonize the effects of estradiol towards ER-α, especially the mutant Y537S type are sought for. Objectives: The focus of this study was the in-silico assessment of the reported secondary metabolites from Phaseolus vulgaris L. (fam. Fabaceae) towards the wild-type and mutant ER-α. Bioisosteric replacement was conducted to generate analogs that can possibly have a comparable binding affinity as estradiol towards estrogen receptors alpha. Results: Majority of the secondary metabolites present in Phaseolus vulgaris L. belong to the group of phytoestrogens, phytosterols, and plant hormones. These groups of compounds exhibited favorable binding energies toward the wild-type and mutant (Y537S) estrogen receptors alpha. Moreover, they bind to the same ligand binding pocket as estradiol, involving similar interactions and amino acid residues. Conclusion Compounds from Phaseolus vulgaris L. can potentially target ER-α. Four gibberellin A19 analogs were generated that exhibited favorable binding towards the wild- and mutant- ER-α and may be further optimized to obtain a promisin gcompound against breast cancer.
Breast Neoplasms ; Molecular Docking Simulation

Background: Hypertension is a worldwide epidemic that has been recognized as the most leading global risk for mortality, with its prevalence associated with increased blood pressure, concomitant risks of cardiovascular and kidney diseases, and major commonality in individuals advanced in age. With the current treatment options for hypertension management, there is still a need to develop therapies that directly target receptors that aid in hypertension treatment. Methodology: The study focused on the in-silico profiling of the reported compounds from Areca catechu L. (fam. Arecaceae) towards the n-domain and c-domain angiotensin converting enzyme (ACE) receptor models. Bioisosteric replacement was used to create bioisosteres investigated for similar binding affinity. Results: Some A. catechu compounds exhibited favorable binding energies towards the n- and c-domain receptor models of ACE, binding in the same ACE ligand binding site as lisinopril, benazepril, and sampatrilat via similar interactions and amino acid residues. The majority of A. catechu compounds with favorable ACE binding energies belong to the phytochemical classes of flavonoids, polyphenols and phenolics, glycosides, and steroids. After in silico toxicity and pharmacokinetic profiling, the bioisosteres Leuco-DM02-39, Leuco-DM02-66, Leuco-DM05-60, Querc-DM09-63, and Querc-DM14-31 with binding energies higher than their parent compounds and comparable to lisinopril, benazepril, and sampatrilat were deemed the best. Conclusion A. catechu compounds have the potential to target ACE n-domain and c-domain receptor models. Three leucocyanidin and two quercetin bioisosteres exhibited favorable binding to the n-domain and c-domain ACE receptor models and could be further optimized to derive a promising antihypertensive agent through ACE inhibition.
Peptidyl-Dipeptidase A ; Areca ; Hypertension

Background: Extended-spectrum beta-lactamases (ESBLs), which allow bacteria to become resistant to commonly used antibiotics against common pathogens such as Klebsiella pneumoniae, are a significant public health concern as their presence severely limits treatment options. Discovery and development of new drug entities are critical to effectively combat infections with these increasingly common antibiotic-resistant variants. Objective: Computational approaches can accelerate and reduce the cost of the discovery phase by screening for inhibitors of “druggable” pathogen enzyme targets in silico. In this study, protein structures of the ESBL enzymes SHV-1 and CTX-M-15 were used as targets in molecular docking experiments to identify potential inhibitors for K. pneumoniae. Methodology: 5000 compounds from the Enamine Real HTS compound database were screened in silico for binding to SHV-1 and CTX-M-15. Twenty-six (26) compounds that were identified to have more favorable interactions compared to Avibactam, a known inhibitor of the target proteins, were tested for cytotoxic activities in vivo using Resazurin Microtiter Assay (REMA) against a K. pneumoniae clinical isolate containing both SHV-1 and CTX-M-15 resistance genes. Results and Conclusion Despite favorable binding energies in in silico screening, most of the compounds exhibited negligible inhibition on the growth of the K. pneumoniae clinical isolate in in vitro assays. This may be attributed to the fact that a phenotypic whole-cell assay, instead of an enzyme-targeted assay, was used for validation. Cell permeability requires a different set of molecular parameters which were not part of the study. Doxorubicin exhibited the highest in vitro bactericidal activity against this strain, which agrees with its known activity against many other bacterial pathogens and may be a promising compound for further lead optimization.
Drug Resistance, Microbial