Publications

2024

1. “Toward Unveiling Putative Binding Sites of Interleukin-33: Insights from Mixed-Solvent Molecular Dynamics Simulations of the Interleukin-1 Family”.
   T. Mai, T.-P. Lam, L.-H. Pham, et al.
   Journal of Physical Chemistry B, vol. 128, no. 35, pp. 8362–8375, 2024
   PDF ABS DOI BIB

   The interleukin (IL)-1 family is a major proinflammatory cytokine family, ranging from the well-studied IL-1s to the most recently discovered IL-33. As a new focus, IL-33 has attracted extensive research for its crucial immunoregulatory roles, leading to the development of notable monoclonal antibodies as clinical candidates. Efforts to develop small molecules disrupting IL-33/ST2 interaction remain highly desired but encounter challenges due to the shallow and featureless interfaces. The information from relative cytokines has shown that traditional binding site identification methods still struggle in mapping cryptic sites, necessitating dynamic approaches to uncover druggable pockets on IL-33. Here, we employed mixed-solvent molecular dynamics (MixMD) simulations with diverse-property probes to map the hotspots of IL-33 and identify potential binding sites. The protocol was first validated using the known binding sites of two IL-1 family members and then applied to the structure of IL-33. Our simulations revealed several binding sites and proposed side-chain rearrangements essential for the binding of a known inhibitor, aligning well with experimental NMR findings. Further microsecond-time scale simulations of this IL-33-protein complex unveiled distinct binding modes with varying occurrences. These results could facilitate future efforts in developing ligands to target challenging flexible pockets of IL-33 and IL-1 family cytokines in general.

   @article{mai2024mixmd,
     title = {Toward Unveiling Putative Binding Sites of Interleukin-33: Insights from Mixed-Solvent Molecular Dynamics Simulations of the Interleukin-1 Family},
     author = {Mai, Tan and Lam, Thua-Phong and Pham, Long-Hung and Nguyen, Kim-Hung and Nguyen, Quoc Thai and Le, Minh Tri and Thai, Khac-Minh},
     journal = {Journal of Physical Chemistry B},
     volume = {128},
     number = {35},
     pages = {8362-8375},
     year = {2024},
     doi = {10.1021/acs.jpcb.4c03057},
     publisher = {American Chemical Society}
   }

2. “Flavonoids as dual-target inhibitors against α-glucosidase and α-amylase: a systematic review of in vitro studies”.
   T.-P. Lam, N.-V. N. Tran, L.-H. D. Pham, et al.
   Natural Products and Bioprospecting, vol. 14, no. 1, p. 4, 2024
   PDF ABS DOI BIB

   Diabetes mellitus remains a major global health issue, and great attention is directed at natural therapeutics. This systematic review aimed to assess the potential of flavonoids as antidiabetic agents by investigating their inhibitory effects on α-glucosidase and α-amylase, two key enzymes involved in starch digestion. Six scientific databases (PubMed, Virtual Health Library, EMBASE, SCOPUS, Web of Science, and WHO Global Index Medicus) were searched until August 21, 2022, for in vitro studies reporting IC50 values of purified flavonoids on α-amylase and α-glucosidase, along with corresponding data for acarbose as a positive control. A total of 339 eligible articles were analyzed, resulting in the retrieval of 1643 flavonoid structures. These structures were rigorously standardized and curated, yielding 974 unique compounds, among which 177 flavonoids exhibited inhibition of both α-glucosidase and α-amylase are presented. Quality assessment utilizing a modified CONSORT checklist and structure–activity relationship (SAR) analysis were performed, revealing crucial features for the simultaneous inhibition of flavonoids against both enzymes. Moreover, the review also addressed several limitations in the current research landscape and proposed potential solutions. The curated datasets are available online at https://github.com/MedChemUMP/FDIGA.

   @article{lam2024flavonoids,
     title = {Flavonoids as dual-target inhibitors against $\alpha$-glucosidase and $\alpha$-amylase: a systematic review of in vitro studies},
     author = {Lam, Thua-Phong and Tran, Ngoc-Vi Nguyen and Pham, Long-Hung Dinh and Lai, Nghia Vo-Trong and Dang, Bao-Tran Ngoc and Truong, Ngoc-Lam Nguyen and Nguyen-Vo, Song-Ky and Hoang, Thuy-Linh and Mai, Tan Thanh and Tran, Thanh-Dao},
     journal = {Natural Products and Bioprospecting},
     volume = {14},
     number = {1},
     pages = {4},
     year = {2024},
     doi = {10.1007/s13659-023-00424-w},
     publisher = {Springer}
   }

2023

1. “Discovery of novel flavonoid derivatives as potential dual inhibitors against α-glucosidase and α-amylase: virtual screening, synthesis, and biological evaluation”.
   T. T. Mai, M.-H. Phan, T. T. Thai, et al.
   Molecular Diversity, pp. 1–22, 2023
   PDF ABS DOI BIB

   Diabetes mellitus is one of the top ten causes of death worldwide, accounting for 6.7 million deaths in 2021, and is one of the most rapidly growing global health emergencies of this century. Although several classes of therapeutic drugs have been invented and applied in clinical practice, diabetes continues to pose a serious and growing threat to public health and places a tremendous burden on those affected and their families. The strategy of reducing carbohydrate digestibility by inhibiting the activities of α-glucosidase and α-amylase is regarded as a promising preventative treatment for type 2 diabetes. In this study, we investigated the dual inhibitory effect against two polysaccharide hydrolytic enzymes of flavonoid derivatives from an in-house chemical database. By combining molecular docking and structure–activity relationship analysis, twelve compounds with docking energies less than or equal to − 8.0 kcal mol−1 and containing required structural features for dual inhibition of the two enzymes were identified and subjected to chemical synthesis and in vitro evaluation. The obtained results showed that five compounds exhibited dual inhibitory effects on the target enzymes with better IC50 values than the approved positive control acarbose. Molecular dynamics simulations were performed to elucidate the binding of these flavonoids to the enzymes. The predicted pharmacokinetic and toxicological properties suggest that these compounds are viable for further development as type 2 diabetes drugs.

   @article{mai2023discovery,
     title = {Discovery of novel flavonoid derivatives as potential dual inhibitors against $\alpha$-glucosidase and $\alpha$-amylase: virtual screening, synthesis, and biological evaluation},
     author = {Mai, Tan Thanh and Phan, Minh-Hoang and Thai, Thao Thi and Lam, Thua-Phong and Lai, Nghia Vo-Trong and Nguyen, Thanh-Thao and Nguyen, Thuy-Viet-Phuong and Vo, Cam-Van Thi and Thai, Khac-Minh and Tran, Thanh-Dao},
     journal = {Molecular Diversity},
     pages = {1--22},
     year = {2023},
     doi = {10.1007/s11030-023-10680-0},
     publisher = {Springer}
   }

2022

1. “Identification of diosmin and flavin adenine dinucleotide as repurposing treatments for monkeypox virus: a computational study”.
   T.-P. Lam, V.-H. Tran, T. T. Mai, et al.
   International Journal of Molecular Sciences, vol. 23, no. 19, p. 11570, 2022
   PDF ABS DOI BIB

   The World Health Organization declared monkeypox a global public health emergency on 23 July 2022. This disease was caused by the monkeypox virus (MPXV), which was first identified in 1958 in Denmark. The MPXV is a member of the Poxviridae family, the Chordopoxvirinae subfamily, and the genus Orthopoxvirus, which share high similarities with the vaccinia virus (the virus used to produce the smallpox vaccine). For the initial stage of infection, the MPXV needs to attach to the human cell surface glycosaminoglycan (GAG) adhesion molecules using its E8 protein. However, up until now, neither a structure for the MPXV E8 protein nor a specific cure for the MPXV exists. This study aimed to search for small molecules that inhibit the MPXV E8 protein, using computational approaches. In this study, a high-quality three-dimensional structure of the MPXV E8 protein was retrieved by homology modeling using the AlphaFold deep learning server. Subsequent molecular docking and molecular dynamics simulations (MDs) for a cumulative duration of 2.1 microseconds revealed that ZINC003977803 (Diosmin) and ZINC008215434 (Flavin adenine dinucleotide-FAD) could be potential inhibitors against the E8 protein with the MM/GBSA binding free energies of −38.19 ± 9.69 and −35.59 ± 7.65 kcal·mol−1, respectively.

   @article{lam2022identification,
     title = {Identification of diosmin and flavin adenine dinucleotide as repurposing treatments for monkeypox virus: a computational study},
     author = {Lam, Thua-Phong and Tran, Viet-Hung and Mai, Tan Thanh and Lai, Nghia Vo-Trong and Dang, Bao-Tran Ngoc and Le, Minh-Tri and Tran, Thanh-Dao and Trinh, Dieu-Thuong Thi and Thai, Khac-Minh},
     journal = {International Journal of Molecular Sciences},
     volume = {23},
     number = {19},
     pages = {11570},
     year = {2022},
     doi = {10.3390/ijms231911570},
     publisher = {MDPI}
   }

2. “Exploration of chalcones as 3-chymotrypsin-like protease (3CLpro) inhibitors of SARS-CoV-2 using computational approaches”.
   T.-P. Lam, D.-N. Nguyen, T. T. Mai, et al.
   Structural Chemistry, vol. 33, no. 5, pp. 1707–1725, 2022
   PDF ABS DOI BIB

   The main protease 3CLpro is one of the potential targets against coronavirus. Inhibiting this enzyme leads to the interruption of viral replication. Chalcone and its derivatives were reported to possess the ability to bind to 3CLpro protease in the binding pocket. This study explored an in-house database of 269 chalcones as 3CLpro inhibitors using in silico screening models, including molecular docking, molecular dynamics simulation, binding free energy calculation, and ADME prediction. C264 and C235 stand out as the two most potential structures. The top hit compound C264 was with the Jamda score of −2.8329 and the MM/GBSA binding energy mean value of −28.23 ± 3.53 kcal/mol, which was lower than the reference ligand. Despite the lower mean binding energy (−22.07 ± 3.39 kcal/mol), in-depth analysis of binding interaction suggested C235 could be another potential candidate. Further, in vitro and in vivo experiments are required to confirm the inhibitory ability.

   @article{Lam2022-ql,
     title = {Exploration of chalcones as 3-chymotrypsin-like protease ({3CLpro}) inhibitors of {SARS-CoV-2} using computational approaches},
     author = {Lam, Thua-Phong and Nguyen, Dac-Nhan and Mai, Tan Thanh and Tran, Thanh-Dao and Le, Minh-Tri and Huynh, Phuong Nguyen Hoai and Nguyen, Duc-Tuan and Tran, Viet-Hung and Trinh, Dieu-Thuong Thi and Truong, Phuong and Vo, Cam-Van T and Thai, Khac-Minh},
     year = {2022},
     journal = {Structural Chemistry},
     volume = {33},
     number = {5},
     pages = {1707--1725},
     publisher = {Springer},
     doi = {10.1007/s11224-022-02000-3},
   }

3. “Small molecules as anti COVID-19 therapeutics: Discovery process, mechanism of action and clinical trials”.
   T. T. Mai, T. P. Lâm, B. N. T. Đặng, et al.
   Science & Technology Development Journal - Health Sciences, 2022
   PDF ABS DOI BIB

   COVID-19 has become a pandemic and is still breaking out in many countries all over the world due to the emergence of new variants. Several safe and effective vaccines have been approved and succeeded in reducing the rate of patients with severe symptoms and that of mortality. Currently, most countries have chosen to change their policy from “zero Covid” to “live with” the pandemic and opened their boundaries to recover their economy. However, the emergence of new dangerous variants such as Delta or Omicron significantly reduces the effectiveness of vaccines and therefore, is complicating the pandemic control. In addition to the use of vaccines, the development of antiviral drugs is extremely important to tackle this worldwide threat. Currently, the approved anti-COVID-19 agents consist of two main categories, including spike protein (S) targeted monoclonal antibodies and orally available small molecule antiviral agents. However, the biopharmaceutical approach still incurs significant drawbacks such as bad bioavailability, expensive and growing resistance of the virus due to the accumulation of mutations in the receptor binding domain (RBD) of the spike protein in new variants. On the other hand, small molecule antiviral agents are a more appealing approach as their main therapeutic targets are intrinsic enzymes which are less likely to mutate, hence remaining inhibitory activity against different variants. Additionally, the oral availability of these drugs also allows these medications to be taken by individuals without the aid of healthcare professionals, which could alleviate the burden on healthcare systems. Therefore, the research and finding of new orally available antiviral agents is still a necessity. This review is carried out to give an overview of the discovery and development, mechanism of action, clinical trials, and approval status of current small-molecule anti-SARS-CoV-2 drugs.

   @article{Mai2022,
     title = {Small molecules as anti COVID-19 therapeutics: Discovery process,  mechanism of action and clinical trials},
     issn = {2734-9446},
     url = {http://dx.doi.org/10.32508/stdjhs.v3i2.515},
     doi = {10.32508/stdjhs.v3i2.515},
     journal = {Science & Technology Development Journal - Health Sciences},
     publisher = {Viet Nam National University Ho Chi Minh City},
     author = {Mai, Thành Tấn and Lâm, Thừa Phong and Đặng, Bảo Ngọc Trân and Võ, Trọng Nghĩa Lại and Thái, Khắc Minh and Trần, Thành Đạo and Nguyễn, Minh Hiền and Nguyễn, Phước Vinh and L\^e, Minh Trí},
     year = {2022}
   }

1. “Identification of Putative Orthosteric and Allosteric Binding Sites of Interleukin-33 using Extensive Molecular Dynamics Simulations”.
   T. Mai, T.-P. Lam, L.-H. Pham, K.-H. Nguyen, and K.-M. Thai.
   9th International Electronic Conference on Medicinal Chemistry 2023, session Emerging technologies in drug discovery
   PDF ABS BIB

   Interleukin (IL)-33, the newest member of the IL-1 family, plays a pivotal role in inflammatory and autoimmune diseases through its protein-protein interaction (PPI) with the ST2 receptor. Targeting this interaction holds promise for disease management. Although the IL-33/ST2 complex crystal structure has been resolved for nearly a decade, no comprehensive investigations into the druggability of IL-33 have been conducted. Furthermore, while several IL-33 inhibitors have been reported, their binding mechanisms have predominantly relied on rudimentary molecular docking approaches. In this study, we sought to identify possible druggable sites on the IL-33 surface using mixed-solvent molecular dynamics (MixMD) simulations and propose the possible mechanism of action of a reported IL-33 inhibitor using extensive-MD simulations. MixMD is an advanced MD technique that not only captures the protein’s flexibility but also considers its interactions with small chemical probes. Our findings revealed five potential druggable sites on the IL-33 surface, two of which overlaid well with the interface of the ST2 receptor. The three remaining sites were investigated for their allosteric potential via all-atom normal mode analysis in the presence of pseudoligands. The current results suggested that interaction with these binding sites could exert possible dynamical change compared to the apoprotein conformation and serve as starting points for IL-33 allosteric modulation. Additionally, the binding modes of an orthosteric IL-33 inhibitor were also extracted and analyzed using the results from a 5-microseconds simulation. Our study can pave the way for future studies aiming to modulate the PPI of IL-33/ST2 employing both orthosteric and allosteric approaches.

   @inproceedings{mai2023mixmd,
     title = {Identification of Putative Orthosteric and Allosteric Binding Sites of Interleukin-33 using Extensive Molecular Dynamics Simulations},
     author = {Mai, Tan and Lam, Thua-Phong and Pham, Long-Hung and Nguyen, Kim-Hung and Thai, Khac-Minh},
     booktitle = {9th International Electronic Conference on Medicinal Chemistry 2023, session Emerging technologies in drug discovery},
     publisher = {MDPI},
     published = {2},
     conference = {1}
   }

2. “Identification of novel inhibitors of interleukin-33 using 3D shape-based similarity approach”.
   T. T. Mai, T.-P. Lam, T.-N. V. Lai, et al.
   Asian Federation for Pharmaceutical Sciences Conference 2023, Drug Design & Analytical methods
   PDF BIB

   @inproceedings{mai2023shape,
     title = {Identification of novel inhibitors of interleukin-33 using 3D shape-based similarity approach},
     author = {Mai, Tan Thanh and Lam, Thua-Phong and Lai, Trong-Nghia Vo and Dang, Bao-Tran Ngoc and Mai, Son-Thach and Nguyen, Lan-Anh and Thai, Khac-Minh},
     booktitle = {Asian Federation for Pharmaceutical Sciences Conference 2023, Drug Design & Analytical methods},
     published = {2},
     conference = {1}
   }