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Fulltext Electrical conductivity of anionic surfactant-doped polypyrrole nanoparticles prepared via emulsion polymerization

Ghalib, H., Abdullah, I., Daik, R.

Pertanika Journal of Science & Technology, 2013;21(2):459-472.
MyJurnal

Conducting polypyrrole (PPy) nanoparticles were synthesized by chemical oxidative polymerization of pyrrole in aqueous solution containing ferric sulfate (Fe2(SO4)3), anionic surfactants (sodium dodecylbenzene-sulfonate (NaDBS) or sodium dodecyl sulfate (SDS)), 1-pentanol as the oxidant, dopant and co-emulsifier, respectively. The polymerization was carried out at 0 ºC and 25 ºC. Fourier transform infrared spectroscopy (FTIR) and elemental analysis indicated that anionic surfactants were successfully incorporated into the PPy backbone. Incorporation of anionic surfactants caused enhanced electrical conductivity, increased yield, decreased the size of particles as well as improved the thermal stability of the resultant PPy. The presence of anionic surfactant seems to inhibit undesirable side reactions so as to improve the regularity of the PPy backbone. Globular PPy particles were obtained with diameter ranged from 40 to 118 nm as revealed by field emission scanning electron microscopy (FE-SEM) and conductivity of 7.89×10-4 –2.35×10-2 S cm-1, as measured using impedance analyzer. It was found that polymerization at low temperature (0 ºC) produced PPy particles with smaller size and higher conductivity. The sodium dodecyl sulfate-doped PPy (SDS-doped PPy) exhibited higher conductivity than that of the sodium dodecylbenzenesulfonate-doped PPy (NaDBS-doped PPy), due to the bulkiness of NaDBS as compared to SDS.
Fulltext Endoscopic transgastric drainage of pseudopancreatic cyst

Bahari HMM, Abdullah I

Med J Malaysia, 1982 Dec;37(4):316-7.
PMID: 7167081

There are many techniques of drainage of a pseudopancreatic cyst. We are describing a new method of drainage by an endoscopic transgastric route.
First-dose response to angiotensin-converting enzyme inhibition in congestive cardiac failure: a Malaysian experience

Navookarasu NT, Rahman AR, Abdullah I

Int J Clin Pract, 1999 Jan-Feb;53(1):25-30.
PMID: 10344062

Despite their proven value in reducing morbidity and mortality in different grades of heart failure, angiotensin converting enzyme (ACE) inhibitors continue to be underused. One reason for this is clinicians' apprehension of first-dose hypotension. We conducted a double-blind, randomised, placebo-controlled parallel group study to investigate the effect of various ACE inhibitors on first-dose hypotension. Eighty unselected patients were randomised into five treatment groups: placebo, captopril 6.25 mg, enalapril 2.5 mg, perindopril 2 mg and lisinopril 2.5 mg. Blood pressure was measured at baseline, half hourly for two hours and hourly for three hours after drug treatment. The maximum drops in mean arterial pressure (in mmHg +/- SD) were placebo 5.89 +/- 2.65, perindopril 5.29 +/- 2.49, enalapril 13.28 +/- 3.31, lisinopril 15.04 +/- 5.74 and captopril 16.76 +/- 5.74 (all p < 0.05 vs placebo except for perindopril). Perindopril, unlike the other ACE inhibitors studied, did not produce first-dose hypotension following its initiation in patients with congestive heart failure.
Fulltext Amoebiasis with multiple colonic perforations and ruptured liver abscess - a case report

Manukaran MN, Ahmad H, Abdullah I

Med J Malaysia, 1983 Mar;38(1):71-3.
PMID: 6633343

A case of amoebiasis with colonic perforation and ruptured liver abscess is reported. It is rare for both these complications to occur in the same patient. The management is described and the literature reviewed
Impact of COVID-19 Pandemic on Pharmacy Education in Malaysia and Indonesia

Efendie B, Abdullah I, Yusuf E

Sr Care Pharm, 2020 Nov 01;35(11):484-486.
PMID: 33121570 DOI: 10.4140/TCP.n.2020.484

The pandemic has affected all walks of life and businesses, including education at all levels. Movement controls have forced the schools and universities to migrate the teaching and learning to be fully online. Some universities in large cities in Malyasia had already implemented blended learning and thus, were better prepared to adjust to the current situation. However, the universities, which practiced mainly traditional didactic courses, were struggling to suddenly change the mode of delivery. Many relied on the creativity of the lecturers and students.
Fulltext Non-pharmacological that most effective to reduce of primary dysmenorrhea intensity in women childbearing age: a literature review

Ilmiah WS, Abdullah I, Koesrini J

J Public Health Afr, 2023 Dec 27;14(12):2349.
PMID: 38204814 DOI: 10.4081/jphia.2023.2349

One of the most common female reproductive health problems is primary dysmenorrhea. Data on the incidence of primary dysmenorrhea complained about 50-90% of women in the world. Primary dysmenorrhea data in the US is 30-70%, in Sweden is 30%, in Mexico is 64%, in Italy is 68%, in Jordan is 55.8%, in Turkey is 84.9%, and in Malaysia is 74.5%, in Indonesia is 60-70 and 15% of its, it interferes with daily activities including work. The cause of this is hypercontractility of the myometrium due to excessive secretion of prostaglandins. This study aims to explore the most effective non-pharmacological therapies in reducing the level of primary dysmenorrhea pain in women of childbearing age. The design of this study is a literature review with the PRISMA method. Database Google, Google Scholar, Research gate, Cochran Data Base, Embase, NCBI, Sciendirect, SAGE, Elsevier, Sinta. The population of this study was all full-text international journals indexed by Scopus and national journals indexed by Sinta 1-6 published in 2011-2021 including RCT amount of 114 articles. A sample of 23 articles meets the inclusion criteria and used thematic data analysis. The results of non-pharmacological therapy that effectively overcome primary dysmenorrhea pain, namely the first group with (P=0.000). The conclusions showed that Murrotal Qur'an, yoga, acupressure, counter pressure massage, effleurage massage, consume green coconut water and avocado juice combination with massage were proven to be equally effective in overcoming complaints of primary dysmenorrhea pain quickly without being accompanied by side effects.
Antibacterial Evaluation of Gallic Acid and its Derivatives against a Panel of Multi-drug Resistant Bacteria

Abdella M, Lahiri C, Abdullah I, Anwar A

Med Chem, 2024;20(2):130-139.
PMID: 37612861 DOI: 10.2174/1573406419666230823104300

BACKGROUND: Infectious diseases are the second leading cause of deaths worldwide. Pathogenic bacteria have been developing tremendous resistance against antibiotics which has placed an additional burden on healthcare systems. Gallic acid belongs to a naturally occurring phenolic class of compounds and is known to possess a wide spectrum of antimicrobial activities.
AIMS & OBJECTIVES: In this study, we synthesized thirteen derivatives of gallic acid and evaluated their antibacterial potential against seven multi-drug resistant bacteria, as well as cytotoxic effects against human embryonic kidney cell line in vitro. Methods: 13 compounds were successfully synthesized with moderate to good yield and evaluated. Synthesized derivatives were characterized by using nuclear magnetic resonance spectroscopy, mass spectrometry, and Fourier transformation infrared spectroscopy. Antibacterial activity was determined using microdilution while cytotoxicyt was assessed using MTT assay.
RESULTS: The results of antibacterial assay showed that seven out of thirteen compounds exhibited antibacterial effects with compound 6 and 13 being most potent against Staphylococcus aureus (MIC 56 μg/mL) and Salmonella enterica (MIC 475 μg/mL) respectively. On the other hand, most of these compounds showed lower cytotoxicity against human embryonic kidney cells (HEK 293), with IC50 values ranging from over 700 μg/mL.
CONCLUSION: Notably, compound 13 was found to be non-toxic at concentrations as high as 5000 μg/mL. These findings suggest that the present synthetic derivatives of gallic acid hold potential for further studies in the development of potent antibacterial agents.
Fulltext Effectiveness of Dual Biologic or Small Molecule Therapy for Achieving Endoscopic Remission in Refractory Inflammatory Bowel Disease

Abdullah I, AlMojil K, Shehab M

Diseases, 2022 Nov 09;10(4).
PMID: 36412596 DOI: 10.3390/diseases10040102

Inflammatory bowel disease (IBD) is a chronic autoimmune disease with relapse-remission courses. A number of patients may present with a refractory disease with partial or no response to treatment. Others may present with extra-intestinal manifestations that makes the treatment with one biologic challenging. Dual target therapy (DTT), combining biologics and/or small molecule drugs, may offer a chance to achieve remission in these cases and improve patients' quality of life despite the limited evidence regarding this approach. We present a case series of refractory inflammatory bowel disease cases managed with DTT. Seven patients with refractory IBD achieved steroid free, clinical, and endoscopic remission by using DTT. These results support that DTT could be an effective approach in selected patients with refractory IBD or with concomitant extra-intestinal manifestations (EIM). Larger studies, ideally randomized controlled trials, are needed to further support the evidence and confirm the efficacy and safety of DTT for IBD.
Citrullus colocynthis (L.) Schrad (bitter apple fruit): a review of its phytochemistry, pharmacology, traditional uses and nutritional potential

Hussain AI, Rathore HA, Sattar MZ, Chatha SA, Sarker SD, Gilani AH

J Ethnopharmacol, 2014 Aug 8;155(1):54-66.
PMID: 24936768 DOI: 10.1016/j.jep.2014.06.011

Citrullus colocynthis (L.) Schrad is a valuable cucurbit plant, widely distributed in the desert areas of the world. Citrullus colocynthis fruits are usually recognized for its wide range of medicinal uses as well as pharmaceutical and nutraceutical potential. This review aims to appraise the published information on the ethnobotanical knowledge, phytochemistry, ethnopharmacology, nutraceutical potential and safety studies of Citrullus colocynthis (bitter apple) fruit, with critical analysis on the gaps and potential for future studies.
Potential of using multiscale kenaf fibers as reinforcing filler in cassava starch-kenaf biocomposites

Zainuddin SY, Ahmad I, Kargarzadeh H, Abdullah I, Dufresne A

Carbohydr Polym, 2013 Feb 15;92(2):2299-305.
PMID: 23399291 DOI: 10.1016/j.carbpol.2012.11.106

Biodegradable materials made from cassava starch and kenaf fibers were prepared using a solution casting method. Kenaf fibers were treated with NaOH, bleached with sodium chlorite and acetic buffer solution, and subsequently acid hydrolyzed to obtain cellulose nanocrystals (CNCs). Biocomposites in the form of films were prepared by mixing starch and glycerol/sorbitol with various filler compositions (0-10 wt%). X-ray diffraction revealed that fiber crystallinity increased after each stage of treatment. Morphological observations and size reductions of the extracted cellulose and CNCs were studied using field emission scanning electron microscopy and transmission electron microscopy. The effects of different treatments and filler contents of the biocomposites were evaluated through mechanical tests. Results showed that the tensile strengths and moduli of the biocomposites increased after each treatment and the optimum filler content was 6%.
Hydrophobic modification of cellulose isolated from Agave angustifolia fibre by graft copolymerisation using methyl methacrylate

Rosli NA, Ahmad I, Abdullah I, Anuar FH, Mohamed F

Carbohydr Polym, 2015 Jul 10;125:69-75.
PMID: 25857961 DOI: 10.1016/j.carbpol.2015.03.002

Graft copolymerisation of methyl methacrylate (MMA) onto Agave angustifolia was conducted with ceric ammonium nitrate (CAN) as the redox initiator. The maximum grafting efficiency was observed at CAN and MMA concentrations of 0.91 × 10(-3) and 5.63 × 10(-2)M, respectively, at 45°C for 3h reaction time. Four characteristic peaks at 2995, 1738, 1440, and 845 cm(-1), attributed to PMMA, were found in the IR spectrum of grafted cellulose. The crystallinity index dropped from 0.74 to 0.46, while the thermal stability improved upon grafting. The water contact angle increased with grafting yield, indicating increased hydrophobicity of cellulose. SEM images showed the grafted cellulose to be enlarged and rougher. The changes in the physical nature of PMMA-grafted cellulose can be attributed to the PMMA grafting in the amorphous regions of cellulose, causing it to expand at the expense of the crystalline component.
Application of polymethylmethacrylate-grafted cellulose as reinforcement for compatibilised polylactic acid/natural rubber blends

Rosli NA, Ahmad I, Anuar FH, Abdullah I

Carbohydr Polym, 2019 Jun 01;213:50-58.
PMID: 30879689 DOI: 10.1016/j.carbpol.2019.02.074

In this study, modified agave cellulose fibre combined by graft copolymerisation with methylmethacrylate was tested as a potential reinforcement for polylactic acid (PLA)-natural rubber/liquid natural rubber blends. Mechanical, morphological, thermal, wetting, and biodegradation characterisations were performed to assess the influence of cellulose-graft-polymethylmethacrylate (cell-g-PMMA) content on the properties of biocomposites. The addition of cell-g-PMMA improved the mechanical properties of the composites because of the chemical interaction between PLA and PMMA. Thermal stability decreased slightly upon cell-g-PMMA addition because of the low thermal stability of PMMA. A soil burial test revealed that the degradation of composites decreased with an increase in the cell-g-PMMA content. However, the weight loss after burial, which directly affected the water absorption capacity, was still higher for the cell-g-PMMA composites than for the polymer alone.
Fulltext Identification of novel human USP2 inhibitor and its putative role in treatment of COVID-19 by inhibiting SARS-CoV-2 papain-like (PLpro) protease

Mirza MU, Ahmad S, Abdullah I, Froeyen M

Comput Biol Chem, 2020 Dec;89:107376.
PMID: 32979815 DOI: 10.1016/j.compbiolchem.2020.107376

Human ubiquitin carboxyl-terminal hydrolase-2 (USP2) inhibitors, such as thiopurine analogs, have been reported to inhibit SARS-CoV papain-like proteases (PLpro). The PLpro have significant functional implications in the innate immune response during SARS-CoV-2 infection and considered an important antiviral target. Both proteases share strikingly similar USP fold with right-handed thumb-palm-fingers structural scaffold and conserved catalytic triad Cys-His-Asp/Asn. In this urgency situation of COVID-19 outbreak, there is a lack of in-vitro facilities readily available to test SARS-CoV-2 inhibitors in whole-cell assays. Therefore, we adopted an alternate route to identify potential USP2 inhibitor through integrated in-silico efforts. After an extensive virtual screening protocol, the best compounds were selected and tested. The compound Z93 showed significant IC50 value against Jurkat (9.67 μM) and MOTL-4 cells (11.8 μM). The binding mode of Z93 was extensively analyzed through molecular docking, followed by MD simulations, and molecular interactions were compared with SARS-CoV-2. The relative binding poses of Z93 fitted well in the binding site of both proteases and showed consensus π-π stacking and H-bond interactions with histidine and aspartate/asparagine residues of the catalytic triad. These results led us to speculate that compound Z93 might be the first potential chemical lead against SARS-CoV-2 PLpro, which warrants in-vitro evaluations.
RNA Sequencing and Bioinformatics Analysis Reveals the Downregulation of DNA Replication Genes by Morindone in Colorectal Cancer Cells

Chee CW, Mohd Hashim N, Abdullah I, Nor Rashid N

Appl Biochem Biotechnol, 2024 Jun;196(6):3216-3233.
PMID: 37642925 DOI: 10.1007/s12010-023-04690-9

Morindone, a natural anthraquinone compound, has been reported to have significant pharmacological properties in different cancers. However, its anticancer effects in colorectal cancer (CRC) and the underlying molecular mechanisms remain obscure. In this study, RNA sequencing was used to assess the differentially expressed genes (DEGs) following morindone treatment in two CRC cell lines, HCT116 and HT29 cells. Functional enrichment analysis of overlapping DEGs revealed that negative regulation of cell development from biological processes and the MAPK signalling pathway were the most significant Gene Ontology terms and Kyoto Encyclopaedia of Genes and Genome pathway, respectively. Seven hub genes were identified among the overlapping genes, including MCM5, MCM6, MCM10, GINS2, POLE2, PRIM1, and WDHD1. All hub genes were found downregulated and involved in DNA replication fork. Among these, GINS2 was identified as the most cancer-dependent gene in both cells with better survival outcomes. Validation was performed on seven hub genes with rt-qPCR, and the results were consistent with the RNA sequencing findings. Collectively, this study provides corroboration of the potential therapeutic benefits and suitable pharmacological targets of morindone in the treatment of CRC.
Competency development for pharmacy: adopting and adapting the FIP global advanced development framework

Al-Haqan A, Waheedi S, Abdullah I, Meilianti S, Shaaban J

Front Med (Lausanne), 2024;11:1442643.
PMID: 39206168 DOI: 10.3389/fmed.2024.1442643

BACKGROUND: Pharmacy education shifts toward competency-based training to meet healthcare demands. This study aims to develop and validate the Kuwait Advanced Competency Framework (KACF) for pharmacists. The study adopts the FIP Global Advanced Development Framework (GADF) to develop a country-specific framework, emphasizing the importance of aligning with global standards while adapting to local contexts. The developed framework builds upon the Kuwait Foundation Competency Framework to address the need for advanced pharmacy services.
METHODS: This is a mixed methods study that employed an "adopt and adapt" approach. The KACF was adopted from the FIP GADF and adapted following four phases. Phase one involved checking and validating the Arabic version of the FIP GADF. Phase two employed a series of focus groups to validate accuracy and relevancy of competency statements. Phase three utilized a workshop with different stakeholders as a final step of validation. Phase four involved a national survey to assess the national pharmacy workforce against the framework competencies. Qualitative feedback from focus groups and workshops informed competencies modifications. Quantitative data were analyzed using descriptive and multiple correspondence analyses (MCA).
RESULTS: The translation phase verified a bilingual framework that could be utilized by pharmacists in Kuwait. The initial and final validation phases identified 20 behavioral statements (out of 22 in the original document) that are relevant to pharmacy practice in Kuwait. The national survey, comprising 169 respondents, validated the KACF's applicability, revealing variations in career stage progression across competency clusters. Findings highlighted associations between career stages and practice settings, offering insights for tailored workforce development strategies.
CONCLUSION: The KACF emerges as a pivotal tool for advancing pharmacy services in Kuwait, aligning with global trends toward competency-based education. Findings underscored the necessity for context-specific approaches in advancing pharmacy practice, providing a comprehensive understanding of competency progression and readiness for advanced roles.
Efficient Semipolar (11-22) 550 nm Yellow/Green InGaN Light-Emitting Diodes on Low Defect Density (11-22) GaN/Sapphire Templates

Li H, Khoury M, Bonef B, Alhassan AI, Mughal AJ, Azimah E, et al.

ACS Appl Mater Interfaces, 2017 Oct 18;9(41):36417-36422.
PMID: 28960058 DOI: 10.1021/acsami.7b11718

We demonstrate efficient semipolar (11-22) 550 nm yellow/green InGaN light-emitting diodes (LEDs) with In0.03Ga0.97N barriers on low defect density (11-22) GaN/patterned sapphire templates. The In0.03Ga0.97N barriers were clearly identified, and no InGaN clusters were observed by atom probe tomography measurements. The semipolar (11-22) 550 nm InGaN LEDs (0.1 mm2 size) show an output power of 2.4 mW at 100 mA and a peak external quantum efficiency of 1.3% with a low efficiency drop. In addition, the LEDs exhibit a small blue-shift of only 11 nm as injection current increases from 5 to 100 mA. These results suggest the potential to produce high efficiency semipolar InGaN LEDs with long emission wavelength on large-area sapphire substrates with economical feasibility.
Optical Properties of Azo-Benzothiazole Side Chain Liquid Crystalline Polymers: Effect of Solvents, Substituents and Temperatures

Dzulkharnien NSF, Karim MR, Zahid NI, Rahman NMMA, Abdullah I, Salleh NM

J Fluoresc, 2019 Jul;29(4):1049-1056.
PMID: 31338718 DOI: 10.1007/s10895-019-02418-9

The optical properties of a series of side chain liquid crystalline polymers (P1-P3) containing azo-benzothiazole mesogen with different terminal substituents (-H, -CH3 and -OCH2CH3) in four organic solvents of varying polarity have been investigated by absorption and fluorescence spectral analysis. Solvatochromic studies of P1-P3 did not show any regular variation on the absorption and emission intensities with changing the polarity of solvent. Theoretical studies were performed based on different solvent correlation methods such as Dimroth-Reichardt and Kamlet-Taft methods to investigate the solute-solvent interactions. Both absorption and emission maxima of investigated polymers were bathochromically shifted with the replacement of sixth position hydrogen atom by electron donating groups in benzothiazole moiety. The emission intensities of the studied polymers showed decreasing trend with increasing temperature.
Determinants of Inadequate Empiric Antimicrobial Therapy in ICU Sepsis Patients in Al-Madinah Al-Munawwarah, Saudi Arabia: A Comparison of Artificial Neural Network and Regression Analysis

Dala Ali AHH, Harun SN, Othman N, Ibrahim B, Abdulbagi OE, Abdullah I, et al.

Antibiotics (Basel), 2023 Aug 10;12(8).
PMID: 37627725 DOI: 10.3390/antibiotics12081305

In the management of sepsis, providing adequate empiric antimicrobial therapy is one of the most important pillars of sepsis management. Therefore, it is important to evaluate the adequacy of empiric antimicrobial therapy (EAMT) in sepsis patients admitted to intensive care units (ICU) and to identify the determinants of inadequate EAMT. The aim of this study was to evaluate the adequacy of empiric antimicrobial therapy in patients admitted to the ICU with sepsis or septic shock, and the determinants of inadequate EAMT. The data of patients admitted to the ICU units due to sepsis or septic shock in two tertiary healthcare facilities in Al-Madinah Al-Munawwarah were retrospectively reviewed. The current study used logistic regression analysis and artificial neural network (ANN) analysis to identify determinants of inadequate empiric antimicrobial therapy, and evaluated the performance of these two approaches in predicting the inadequacy of EAMT. The findings of this study showed that fifty-three per cent of patients received inadequate EAMT. Determinants for inadequate EAMT were APACHE II score, multidrug-resistance organism (MDRO) infections, surgical history (lower limb amputation), and comorbidity (coronary artery disease). ANN performed as well as or better than logistic regression in predicating inadequate EAMT, as the receiver operating characteristic area under the curve (ROC-AUC) of the ANN model was higher when compared with the logistic regression model (LRM): 0.895 vs. 0.854. In addition, the ANN model performed better than LRM in predicting inadequate EAMT in terms of classification accuracy. In addition, ANN analysis revealed that the most important determinants of EAMT adequacy were the APACHE II score and MDRO. In conclusion, more than half of the patients received inadequate EAMT. Determinants of inadequate EAMT were APACHE II score, MDRO infections, comorbidity, and surgical history. This provides valuable inputs to improve the prescription of empiric antimicrobials in Saudi Arabia going forward. In addition, our study demonstrated the potential utility of applying artificial neural network analysis in the prediction of outcomes in healthcare research.
Fulltext Catalytic activity of ethylbenzene with product selectivity by gold nanoparticles supported on zinc oxide

Anwar A, Ma'amor A, Mahmud HNME, Basirun WJ, Abdullah I

Turk J Chem, 2022;46(3):730-746.
PMID: 37720623 DOI: 10.55730/1300-0527.3363

The oxidation of ethylbenzene (EB) using tert-butyl hydroperoxide as the oxidizing agent was carried out in presence of gold nanoparticles (3 nm) supported on zinc oxide in acetonitrile solution. A higher selectivity towards acetophenone (ACP) as the major product, and a moderate selectivity towards other products such as 1-phenylethanol (PE), benzaldehyde (BZL), and benzoic acid (BzA) were observed using the prepared Au/ZnO nanocatalysts at 100 °C for 24 h. It is suggested the reaction produces an intermediate product, which is dimethylethyl-1-phenylethyl peroxide through a radical mechanism. A small amount of benzaldehyde was observed because benzaldehyde went autoxidation to form benzoic acid with the presence of oxidation agent of TBHP during reaction. The factors affecting the catalytic activity such as gold loading, calcination treatment at 300°C, type of solvent, reaction time, reaction temperature, oxidant to substrate molar ratio, catalyst weight, and solvent volume were studied. The gold nanoparticle catalyst synthesized by deposition precipitation method using urea was characterized by XRD, HRTEM, ATR-IR, XRF, and BET and offers a very selective reaction pathway for the oxidation of ethylbenzene.
Fulltext Fragment-based in silico design of SARS-CoV-2 main protease inhibitors

Ahmad S, Usman Mirza M, Yean Kee L, Nazir M, Abdul Rahman N, Trant JF, et al.

Chem Biol Drug Des, 2021 Oct;98(4):604-619.
PMID: 34148292 DOI: 10.1111/cbdd.13914

3CLpro is essential for SARS-CoV-2 replication and infection; its inhibition using small molecules is a potential therapeutic strategy. In this study, a comprehensive crystallography-guided fragment-based drug discovery approach was employed to design new inhibitors for SARS-CoV-2 3CLpro. All small molecules co-crystallized with SARS-CoV-2 3CLpro with structures deposited in the Protein Data Bank were used as inputs. Fragments sitting in the binding pocket (87) were grouped into eight geographical types. They were interactively coupled using various synthetically reasonable linkers to generate larger molecules with divalent binding modes taking advantage of two different fragments' interactions. In total, 1,251 compounds were proposed, and 7,158 stereoisomers were screened using Glide (standard precision and extra precision), AutoDock Vina, and Prime MMGBSA. The top 22 hits having conformations approaching the linear combination of their constituent fragments were selected for MD simulation on Desmond. MD simulation suggested 15 of these did adopt conformations very close to their constituent pieces with far higher binding affinity than either constituent domain alone. These structures could provide a starting point for the further design of SARS-CoV-2 3CLpro inhibitors with improved binding, and structures are provided.

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