Pharmaceutical Properties Research Articles

First Optimization of Novel, Potent, Selective PDE11A4 Inhibitors for Age-Related Cognitive Decline.

Phosphodiesterase 11A4 (PDE11A4) is a dual-acting cyclic nucleotide hydrolase expressed in neurons in the CA1, subiculum, amygdalostriatal transition area and amygdalohippocampal area of the extended hippocampal formation. PDE11A4 is the only PDE enzyme to emanate solely from hippocampal formation, a key brain region for the formation of long-term memory. PDE11A4 expression increases in the hippocampal formation of both humans and rodents as they age. Interestingly, PDE11A knockout mice do not show age-related deficits in associative memory and show no gross histopathology. This suggests that inhibition of PDE11A4 might serve as a therapeutic option for age-related cognitive decline. A novel, yeast-based high throughput screen previously identified moderately potent, selective PDE11A4 inhibitors, and this work describes initial efforts that improved potency more than 10-fold and improved some pharmaceutical properties of one of these scaffolds, leading to selective, cell-penetrant PDE11A4 inhibitors, one of which is 10-fold more potent compared to tadalafil in cell-based activity.

Bowiea volubilis: From "Climbing Onion" to Therapeutic Treasure-Exploring Human Health Applications.

Bowiea volubilis subsp. volubilis is primarily used to address human respiratory infections, coughs, and colds due to its diverse pharmaceutical properties. Notably, the plant contains alkaloids that exhibit notable antifungal, antibacterial, and cytotoxic properties. Additionally, the presence of saponins, with recognized antioxidant and anticancer attributes, further contributes to its medicinal potential. Steroid compounds inherent to the plant have been associated with anti-inflammatory and anticancer activities. Moreover, the bulb of B. volubilis has been associated as a source of various cardiac glycosides. Despite these therapeutic prospects, B. volubilis remains inedible due to the presence of naturally occurring toxic substances that pose risks to both animals and humans. The review focuses on a comprehensive exploration concerning B. volubilis ethnobotanical applications, phytochemical properties, and diverse biological activities in relation to in vitro and in vivo applications for promoting human health and disease prevention. The aim of the study is to comprehensively investigate the phytochemical composition, bioactive compounds, and potential medicinal properties of Bowiea volubilis, with the ultimate goal of uncovering its therapeutic applications for human health. This review also highlights an evident gap in research, i.e., insufficient evidence-based research on toxicity data. This void in knowledge presents a promising avenue for future investigations, opening doors to expanded inquiries into the properties and potential applications of B. volubilis in the context of human diseases.

Reexamining the effects of drug loading on the in vivo performance of PEGylated liposomal doxorubicin.

Higher drug loading employed in nanoscale delivery platforms is a goal that researchers have long sought after. But such viewpoint remains controversial because the impacts that nanocarriers bring about on bodies have been seriously overlooked. In the present study we investigated the effects of drug loading on the in vivo performance of PEGylated liposomal doxorubicin (PLD). We prepared PLDs with two different drug loading rates: high drug loading rate, H-Dox, 12.9% w/w Dox/HSPC; low drug loading rate, L-Dox, 2.4% w/w Dox/HSPC (L-Dox had about 5 folds drug carriers of H-Dox at the same Dox dose). The pharmaceutical properties and biological effects of H-Dox and L-Dox were compared in mice, rats or 4T1 subcutaneous tumor-bearing mice. We showed that the lowering of doxorubicin loading did not cause substantial shifts to the pharmaceutical properties of PLDs such as in vitro and in vivo stability (stable), anti-tumor effect (equivalent effective), as well as tissue and cellular distribution. Moreover, it was even more beneficial for mitigating the undesired biological effects caused by PLDs, through prolonging blood circulation and alleviating cutaneous accumulation in the presence of pre-existing anti-PEG Abs due to less opsonins (e.g. IgM and C3) deposition on per particle. Our results warn that the effects of drug loading would be much more convoluted than expected due to the complex intermediation between nanocarriers and bodies, urging independent investigation for each individual delivery platform to facilitate clinical translation and application.

A Comprehensive review of Nigella sativa (kalonji) from the Unani perspective

The remarkable therapeutic properties of Nigella sativa, often known as black seed or kalonji are well recognized. The use of N. sativa seeds and its oil has a long history in various traditional food and medical systems. As stated by the holy prophet of Islam (PBUH), Shoneez is important since it can cure all diseases with the exception of death. It is widely used in several conventional medical systems, including Unani Tibb, Chinese medicine, Ayurveda, and Siddha.
 The goal of the current review is to provide a thorough overview of the literature on scientific studies of the pharmacognostical properties, chemical makeup, and pharmacological activity of the seeds of this plant.
 The data was collected from various reputed data bases like PubMed, Science direct, Web of Saciences, Google Scholar and Research Gate. The traditional and Unani literature was also searched from the classical books of Greco-Arab medicine in addition to other digital sources.
 According to traditional Unani literature, N. sativa exhibits a variety of pharmacological properties, including those that are carminative, anti-inflammatory, analgesic, diuretic, emmenagogue, galactagogue, and expectorant. Numerous phytochemical, pharmaceutical, and clinical studies have been conducted on N. sativa, revealing its potential anti-diabetic, anti-cancer, immunomodulator, analgesic, antimicrobial, anti-inflammatory, bronchodilator, renal protective, gastro-protective, antioxidant, and other properties. N. sativa is among the top-ranked evidence-based herbal medications because of its remarkable healing ability. The main bioactive component of the essential oil, thymoquinone, is responsible for the majority of its medicinal capabilities.
 Nigella sativa is a potent herb which exhibits wide range of pharmaceutical properties, most of which have been confirmed via preclinical and clinical studies. This review may thus be useful for the research community in particular and common people in general to avail the benefits of N. sativa.
 Keywords: Anti-cancer, Kalonji, Habat-ul-Sauda, Shoneez, Thymoquinone, Nigella sativa, Unani

Spices as Sustainable Food Preservatives: A Comprehensive Review of Their Antimicrobial Potential.

Throughout history, spices have been employed for their pharmaceutical attributes and as a culinary enhancement. The food industry widely employs artificial preservatives to retard the deterioration induced by microbial proliferation, enzymatic processes, and oxidative reactions. Nevertheless, the utilization of these synthetic preservatives in food products has given rise to significant apprehension among consumers, primarily stemming from the potential health risks that they pose. These risks encompass a spectrum of adverse effects, including but not limited to gastrointestinal disorders, the disruption of gut microbiota, allergic reactions, respiratory complications, and concerns regarding their carcinogenic properties. Consequently, consumers are displaying an increasing reluctance to purchase preserved food items that contain such additives. Spices, known for their antimicrobial value, are investigated for their potential as food preservatives. The review assesses 25 spice types for their inherent antimicrobial properties and their applicability in inhibiting various foodborne microorganisms and suggests further future investigations regarding their use as possible natural food preservatives that could offer safer, more sustainable methods for extending shelf life. Future research should delve deeper into the use of natural antimicrobials, such as spices, to not only replace synthetic preservatives but also optimize their application in food safety and shelf-life extension. Moreover, there is a need for continuous innovation in encapsulation technologies for antimicrobial agents. Developing cost-effective and efficient methods, along with scaling up production processes, will be crucial to competing with traditional antimicrobial options in terms of both efficacy and affordability.

Comparison of pharmaceutical properties and biological activities of prednisolone, deflazacort, and vamorolone in DMD disease models.

Duchenne muscular dystrophy (DMD) is a progressive disabling X-linked recessive disorder that causes gradual and irreversible loss of muscle, resulting in early death. The corticosteroids prednisone/prednisolone and deflazacort are used to treat DMD as the standard of care; however, only deflazacort is FDA approved for DMD. The novel atypical corticosteroid vamorolone is being investigated for treatment of DMD. We compared the pharmaceutical properties as well as the efficacy and safety of the three corticosteroids across multiple doses in the B10-mdx DMD mouse model. Pharmacokinetic studies in the mouse and evaluation of p-glycoprotein (P-gP) efflux in a cellular system demonstrated that vamorolone is not a strong P-gp substrate resulting in measurable central nervous system (CNS) exposure in the mouse. In contrast, deflazacort and prednisolone are strong P-gp substrates. All three corticosteroids showed efficacy, but also side effects at efficacious doses. After dosing mdx mice for two weeks, all three corticosteroids induced changes in gene expression in the liver and the muscle, but prednisolone and vamorolone induced more changes in the brain than did deflazacort. Both prednisolone and vamorolone induced depression-like behavior. All three corticosteroids reduced endogenous corticosterone levels, increased glucose levels, and reduced osteocalcin levels. Using micro-computed tomography, femur bone density was decreased, reaching significance with prednisolone. The results of these studies indicate that efficacious doses of vamorolone, are associated with similar side effects as seen with other corticosteroids. Further, because vamorolone is not a strong P-gp substrate, vamorolone distributes into the CNS increasing the potential CNS side-effects.

Variability in Phytochemical Contents and Biological Activities among Adenophora triphylla Genotypes

Genetic diversity can remarkably impact the quality of derived products. This study focused on Adenophora triphylla, an herbaceous perennial used in East Asian traditional medicine. It is known for its diverse therapeutic effects that are attributed to phytochemicals. However, despite its therapeutic potential, a comprehensive exploration of the influence of genetic diversity on the pharmaceutical properties of various A. triphylla genotypes remains unknown. To address this knowledge gap, we employed DNA barcoding regions (ITS2, matK, and psbA-trnH) to elucidate the genetic diversity among the collected genotypes. The combined application of these barcoding regions is a robust method to identify A. triphylla genotypes. In addition, leaf extracts consistently exhibited higher antioxidant potential than root extracts. Nitric oxide production was strongly inhibited by the leaf extracts of the BG genotype (IC50 = 124.52 ± 12.97 µg/mL), and the leaf extracts (200 µg/mL) of the BT genotype contained significant antimelanogenic properties (IC50 = 181.56 ± 16.17 µg/mL). Various genotypes displayed diverse levels of phytochemical content, and the total saponin content exhibited a strong correlation with various biological activities of A. triphylla, suggesting a genetic influence on their pharmaceutical attributes. These findings highlight the significance of genotype selection for optimizing health benefits and promoting the potential utilization of specific genotypes in various industries, such as cosmetics and pharmaceuticals.

Mucoadhesive Alginate/Pectin Films Crosslinked by Calcium Carbonate as Carriers of a Model Antifungal Drug-Posaconazole.

The mucosal membrane of the oral cavity, due to its unique structure and availability, constitutes an appropriate site for the delivery of drugs, both with local and systemic effects. Mucoadhesive buccal films are drug dosage forms that due to their convenience of application, flexibility and size, are characterized by patients' compliance. Sodium alginate and pectin are natural polymers from the polysaccharides group, with mucoadhesive properties, that are widely applied to obtain buccal films. However, their hydrophilic nature and poor water resistance limit their application in sustained drug release formulations. Hence, the aim of this investigation was to design alginate/pectin buccal films by a one-step crosslinking technique-with the application of calcium carbonate. This technique was applied to prepare crosslinked alginate and alginate/pectin mucoadhesive films with a model antifungal drug-posaconazole. The obtained formulations were evaluated for the impact of crosslinking and pectin's presence on their pharmaceutical, mucoadhesive, mechanical and physicochemical properties. Additionally, the antifungal activity of the prepared films against Candida spp. was evaluated. It was shown that pectin's presence in the formulations improved flexibility, mucoadhesion and antifungal activity. The crosslinking process reduced mucoadhesiveness and antifungal activity but significantly enhanced the mechanical properties and stability and enabled prolonged drug release.

Nanofibers of Glycyrrhizin/Hydroxypropyl-β-Cyclodextrin Inclusion Complex: Enhanced Solubility Profile and Anti-inflammatory Effect of Glycyrrhizin.

Despite having a wide range of therapeutic advantages, glycyrrhizin (GL) has few commercial applications due to its poor aqueous solubility. In this study, we combined the benefits of hydroxypropyl β-cyclodextrin (HP-βCD) supramolecular inclusion complexes and electrospun nanofibers to improve the solubility and therapeutic potential of GL. A molecular inclusion complex containing GL and HP-βCD was prepared by lyophilization at a 1:2 molar ratio. GL and hydroxypropyl β-cyclodextrin inclusion complexes were also incorporated into hyaluronic acid (HA) nanofibers. Prepared NF was analyzed for physical, chemical, thermal, and pharmaceutical properties. Additionally, a rat model of carrageenan-induced hind paw edema and macrophage cell lines was used to evaluate the anti-inflammatory activity of GL-HP-βCD NF. The DSC and XRD analyses clearly showed the amorphous state of GL in nanofibers. In comparison to pure GL, GL-HP-βCD NF displayed improved release (46.6 ± 2.16% in 5min) and dissolution profiles (water dissolvability ≤ 6s). Phase solubility results showed a four-fold increase in GL solubility in GL-HP-βCD NF. In vitro experiments on cell lines showed that inflammatory markers like IL-1β, TNF-α, and IL-6 were significantly lower in GL-HP-βCD NF compared to pure GL (p < 0.01 and p < 0.05). According to in vivo results, the prepared nanofiber exhibits a better anti-inflammatory effect than pure GL (63.4% inhibition vs 53.7% inhibition). The findings presented here suggested that GL-HP-βCD NF could serve as a useful strategy for improving the therapeutic effects of GL.

Sesame (Sesamum indicum L.): A Potential Allelopathic Crop - A Review

Sesame (Sesamum indicum L.) is one the oldest oilseed crop cultivated in India. It is cultivated as third crop in summer rice fallows or in marginal lands. Seeds of sesame are used for the extraction of oil, that contain many pharmaceutical and cosmetic properties. Research findings revealed that sesame contains many allelochemicals. The present review focuses on the allelopathic effect of sesame on weeds and crops. Exploring the allelopathic potential of sesame would help to develop bio-herbicides in future and reduce the use of synthetic herbicides in weed management. In addition to this, study on allelopathy of sesame would help to select suitable crops in rotation which are compatible to the sesame.

Design and Construction of Antibody Fusion Proteins Incorporating Variable New Antigen Receptor (VNAR) Domains.

Antibody therapeutics have become a cornerstone of the pharmaceutical market due to their precise molecular targeting, favorable pharmacokinetic properties, and multitiered mechanisms of action. Since the first monoclonal antibody was clinically approved 35years ago, there have been considerable advances in antibody technology. A major breakthrough has been the design of multispecific antibodies and antibody fusion proteins, which introduce the possibility of recognizing two or more targets with a single molecule. However, despite tremendous progress in the antibody engineering field, challenges in formulation, stability, and tissue penetration necessitate the design of novel antibody formats with improved pharmaceutical properties. There is a growing interest in development of single-domain antibodies, which harbor advantages such as high solubility, robust thermostability, and unique geometries that allow for access to cryptic epitopes. Chondrichthyes such as sharks and rays provide a source of single-domain antibody fragments known as variable new antigen receptors (VNARs), which have been exploited as molecular targeting agents. Here, we describe methods to engineer antibody fusion proteins that incorporate VNARs. We present multiple fusion topologies, and detail the design, expression, and purification for each format. These novel antibody fusion proteins hold great promise for a range of applications in biomedical research and therapeutic design.

Optimization of Inulin Extraction from Chicory Roots and an Ultrafiltration Application to Obtain Purified Inulin and Hydrolyzed Fructooligosaccharides

Inulin and fructooligosaccharides (FOS) are prominent functional components in the food industry due to prebiotic and other pharmaceutical properties. Inulin is a storage polysaccharide in various plants. FOS are naturally present in various plants and can be obtained by partial hydrolysis of inulin. In this study, ground and sieved chicory roots (Cichorium intybus L.) were used as starting material for inulin extraction under optimized conditions determined by Response Surface Methodology (RSM) with a Box-Behnken design. Optimum inulin extraction conditions from chicory roots were; temperature of 90 °C, extraction time of 30 min., and liquid-to-solid (LS) ratio of 10:1 mL/g. Inulin extract was further hydrolyzed to FOS by enzymatic or acid treatment, separately. Purification of inulin extract and FOS hydrolysate was performed by ultrafiltration with a 10 kDa membrane under the pressure of 2 bar with continuous stirring. As a result, inulin and FOS were obtained at 90% and 76% purity, respectively.

Therapeutic potential of dietary phytochemicals from Drynaria quercifolia to modulate gut microbiome: an in silico approach

Drynaria quercifolia is one of the pioneer medicinal plants which exert many beneficial effects on humans. Fatty acids are hydrophobic ligands that act as membrane substrates, metabolic signalling molecules, and metabolic energy sources. It could enhance the mucus production in the intestine which maintain mucosal homeostasis. The inflammatory responses were also regulated by 5-HT receptors. Serotonin 2 A receptors are G-protein coupled receptors targeted by various types of ligands viz. antidepressants, antipsychotics and anti-migraine drugs. The interaction of mucin protein and fatty acid could increase the antimicrobial activity and anti-inflammatory activity of gut microbiome. In this study, dietary phytochemicals were extracted from D. quercifolia and characterized using GC-MS analysis. The result shows presence of 38 various compounds viz. decanoic acid, indole, and dodecanoic acid and etc., Among the all, dodecanoic acid showed good drug likeness and pharmaceutical properties. Target proteins viz. 3IFB (Intestinal fatty acid binding protein) and 7WC4 (5-hydroxytryptamine receptor 2 A) were docked with dodecanoic acid using Auto dock software. The fatty acids produced in the gut could interact with 3IFB and 7WC4 proteins to maintain intestinal integrity and improved gut-brain function respectively. Dodecanoic acid exhibits the highest binding energy with mutated 3IFB (-6.01) than native whereas 7WC4 native protein showed (-7.3 kal/mol) the highest affinity than mutated protein. Structural changes were predicted by using SOPMA and ProSA. Evaluation results indicate that 3IFB was having more stability, good quality, and enhanced affinity than 7WC4. Further, MD simulations were done for 3IFB to check the stability of protein-ligand complex using WebGro platform. The model was investigated by root mean square deviation and fluctuations. Therefore, dodecanoic acids have been considered as a potential agonists and offer opportunities for developing innovative medications for gastrointestinal diseases. Communicated by Ramaswamy H. Sarma

Edible Lepidoptera as human foods – a comprehensive review

Abstract As the global population continues to grow, traditional protein sources like meat and fish are becoming increasingly unsustainable due to their environmental impact. Edible insects, on the other hand, are highly nutritious, require minimal resources to produce, and emit significantly fewer greenhouse gases than traditional livestock. Lepidoptera, one of the most diverse insect orders, contains some popular edible species that have been consumed traditionally for centuries across the globe. Based on this review, about 24 families with a total of about 350 edible lepidopteran species were recorded. They are often praised for their excellent nutritional value, such as having high protein and healthy fat content. Edible lepidopterans also contain minerals, essential amino acids, and vitamins, making them a nutritious addition to a balanced diet. They also contain bioactive compounds which have various nutraceutical and pharmaceutical properties. Furthermore, some edible lepidopterans can be farmed and require minimal space and resources. However, there are significant challenges associated with their use as food. One of the primary challenges is the lack of regulations governing their production and distribution, which creates uncertainty for consumers and businesses alike. Consumer acceptance is also a significant barrier to the widespread adoption of insects as food. To overcome these challenges, there is a need for clear regulations that ensure the safety and quality of insect-based products. Furthermore, it is important to raise awareness about the nutritional and environmental benefits of edible insects as sustainable food for the future to promote their acceptance among consumers.

Manganese-doped albumin-gelatin composite nanogel loaded with berberine applied to the treatment of gouty arthritis in rats via a SPARC-dependent mechanism

In this study, manganese-doped albumin-gelatin composite nanogels (MAGN) were prepared and used to load berberine (Ber) for the treatment of gouty arthritis (GA). The nanodrug delivery system (Ber-MAGN) can target inflammatory joints due to the intrinsic high affinity of albumin for SPARC, which is overexpressed at the inflammatory site of GA. Characterization of the pharmaceutical properties in vitro showed that Ber-MAGN had good dispersion, and the particle size was 121 ± 10.7 nm. The sustained release effect significantly improved the bioavailability of berberine. In vitro and in vivo experimental results showed that Ber-MAGN has better therapeutic effects in relieving oxidative stress and suppressing inflammation. Therefore, Ber-MAGN, as a potential pharmaceutical preparation for GA, provides a new reference for the clinical treatment plan of GA.

One Step In Situ Co-Crystallization of Dapsone and Polyethylene Glycols during Fluidized Bed Granulation.

Several studies have demonstrated the feasibility of in situ co-crystallization in different pharmaceutical processes such as spray drying, hot melt extrusion, and fluidized bed granulation (FBG) to produce co-crystal-in-excipient formulations. However, no previous studies have examined such a one step in situ co-crystallization process for co-crystal formulations where the coformer is a polymer. In the current study, we explored the use of FBG to produce co-crystal granules of dapsone (DAP) and different molecular weight polyethylene glycols (PEGs). Solvent evaporation (SE) was proven to generate DAP-PEGs co-crystals at a particular weight ratio of 55:45 w/w between DAP and PEG, which was subsequently used in FBG, using microcrystalline cellulose and hydroxypropyl methyl cellulose as filler excipient and binder, respectively. FBG could generate co-crystals with higher purity than SE. Granules containing DAP-PEG 400 co-crystal could be prepared without any additional binder. DAP-PEG co-crystal granules produced by FBG demonstrated superior pharmaceutical properties, including flow properties and tableting properties, compared to DAP and DAP-PEG co-crystals prepared by SE. Overall, in situ co-crystallization via FBG can effectively produce API-polymer co-crystals and enhance the pharmaceutical properties.

Understanding the chemical reactivity and biological properties of patellamides using theoretical and computational methods

Patellamides are cyclic peptides produced by marine cyanobacteria with potential pharmaceutical properties. Chemical Reactivity Theory, specifically Conceptual DFT-based Computational Peptidology (CDFT-CP), can predict the electronic and structural properties of peptides, as well as their intrinsic chemical reactivity features and aid in designing new peptide-based drugs. Computational ADMET can complement these predictions by evaluating how the drug will behave in the body. This study reports on the results of a CDFT-CP and Computational Pharmacokinetics analysis of Patellamides A–G, including their predicted chemical reactivity descriptors, biological targets, bioactivity radars and ADMET parameters. These tools provide a powerful approach for understanding peptide properties and developing new drugs.

Optimized solubility and bioavailability of genistein based on cocrystal engineering

With various potential health-promoting bioactivities, genistein has great prospects in treatment of a series of complex diseases and metabolic syndromes such as cancer, diabetes, cardiovascular diseases, menopausal symptoms and so on. However, poor solubility and unsatisfactory bioavailability seriously limits its clinical application and market development. To optimize the solubility and bioavailability of genistein, the cocrystal of genistein and piperazine was prepared by grinding assisted with solvent based on the concept of cocrystal engineering. Using a series of analytical techniques including single-crystal X-ray diffraction, powder X-ray diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry and thermogravimetric analysis, the cocrystal was characterized and confirmed. Then, structure analysis on the basis of theoretical calculation and a series of evaluation on the stability, dissolution and bioavailability were carried out. The results indicated that the cocrystal of genistein and piperazine improved the solubility and bioavailability of genistein. Compared with the previous studies on the cocrystal of genistein, this is a systematic and comprehensive investigation from the aspects of preparation, characterization, structural analysis, stability, solubility and bioavailability evaluation. As a simple, efficient and green approach, cocrystal engineering can pave a new path to optimize the pharmaceutical properties of natural products for successful drug formulation and delivery.Graphical

Arginine Gemini-Based Surfactants for Antimicrobial and Antibiofilm Applications: Molecular Interactions, Skin-Related Anti-Enzymatic Activity and Cytotoxicity.

The antimicrobial and antibiofilm properties of arginine-based surfactants have been evaluated. These two biological properties depend on both the alkyl chain length and the spacer chain nature. These gemini surfactants exhibit good activity against a wide range of bacteria, including some problematic resistant microorganisms such us methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. Moreover, surfactants with a C10 alkyl chain and C3 spacer inhibit the (MRSA) and Pseudomonas aeruginosa biofilm formation at concentrations as low as 8 µg/mL and are able to eradicate established biofilms of these two bacteria at 32 µg/mL. The inhibitory activities of the surfactants over key enzymes enrolled in the skin repairing processes (collagenase, elastase and hyaluronidase) were evaluated. They exhibited moderate anti-collagenase activity while the activity of hyaluronidase was boosted by the presence of these surfactants. These biological properties render these gemini arginine-based surfactants as perfect promising candidates for pharmaceutical and biological properties.

Interface Engineering of Carrier-Protein-Dependent Metabolic Pathways.

Carrier-protein-dependent metabolic pathways biosynthesize fatty acids, polyketides, and non-ribosomal peptides, producing metabolites with important pharmaceutical, environmental, and industrial properties. Recent findings demonstrate that these pathways rely on selective communication mechanisms involving protein-protein interactions (PPIs) that guide enzyme reactivity and timing. While rational design of these PPIs could enable pathway design and modification, this goal remains a challenge due to the complex nature of protein interfaces. Computational methods offer an encouraging avenue, though many score functions fail to predict experimental observables, leading to low success rates. Here, we improve upon the Rosetta score function, leveraging experimental data through iterative rounds of computational prediction and mutagenesis, to design a hybrid fatty acid-non-ribosomal peptide initiation pathway. By increasing the weight of the electrostatic score term, the computational protocol proved to be more predictive, requiring fewer rounds of iteration to identify mutants with high in vitro activity. This allowed efficient design of new PPIs between a non-ribosomal peptide synthetase adenylation domain, PltF, and a fatty acid synthase acyl carrier protein, AcpP, as validated by activity and structural studies. This method provides a promising platform for customized pathway design, establishing a standard for carrier-protein-dependent pathway engineering through PPI optimization.