Repuroising Of Fda Approved Thiothixine a Typical Antipychotic Agent as A Pde-5 Inhbitor For Erectile Dysfunction

Erectile dysfunction (ED) is a very common clinical disorder that affects millions of men worldwide and increases with age. [1] The psychosocial consequences of the clinical disorder goes beyond the physical aspects and also has consequences on psychological health, functioning in relationships, and overall wellbeing. [2]The pathophysiology of ED is complex, with many physical, psychological and lifestyle factors, sometimes overlapping in a way that it can be difficult to determine the apparent causes.[3] Factors contributing to the presentation of ED includes medical conditions such as cardiovascular disease, diabetes and anxiety, as well lifestyle risk factors such as smoking and alcohol use.[4] Because ED can be multifactorial, treatment of the condition may also be offered in multiple ways, including multiple symptom management and/or outcomes.[5] Phosphodiesterase type 5 (PDE-5) inhibitors have become the most common pharmacologic treatment for ED during the last several decades.[6] PDE-5 inhibitors work by improving the physiological mechanism of erection, most commonly by inhibiting the PDE-5 enzyme that is responsible for regulating blood flow to the penis.[7] Medications such as Sildenafil (Viagra), Tadalafil (Cialis) and others have markedly changed the treatment of ED and allowed the provision of a means of treatment that is relatively effective and less invasive than previous clinical options.[8] However, treatment is not effective for all men, and some patients may encounter side effects or a significant ED may not respond to PDE-5 inhibitors.[9] Under the previous structured framework it is important to examine and identify new treatment opportunities for erectile dysfunction (ED), using an alternative pharmacological agent that already has its license and abuse the safety and efficacy data that is associated with it[10]. One such candidate, with strong support and history is Thiothixene (e.g. Navane), which is a first-generation antipsychotic used to treat patients with schizophrenia and related disorders. [11] The mechanism of action of Thiothixene is to produce its antipsychotic effects by blocking dopamine receptors and reducing symptoms of psychosis (e.g., delusion and hallucinations) [12]. Although it is an antipsychotic and typically regarded as a neuroleptic drug it has profiles that involve the action of a number of neurotransmitter systems, full exploration of its potential additional uses has not taken place.[13] We will therefore hypothesize in this article, that it is possible that the agent, Thiothixene, can act against phosphodiesterase (PDE-5) and therefore contribute to expanding its therapeutic indications to include ED.[14] However, the tone of repurposing existing drugs in already licenced agents adds an encouragement, drug repurposing is when existing drugs are investigated to determine any other possible uses to repurpose to due the established indications.[15]  As a first line ED treatment, then, it is worthy to examine PDE-5 inhibition through Thiothixene particularly with itchy patients that cannot be treated by other PDE-5 inhibitors or cannot tolerate medication.[16] In this introduction section, we will discuss ED prevalence and causes, and the role PDE-5 Inhibitors play in current treatment guidelines.[17] We will then provide a thorough theoretical brief of Thiothixenes pharmacological profile as an antipsychotic including its mechanism of action and current clinical applications.[18] Lastly, we will share our hypothesis that Thiothixene's array of pharmacological effects as an excellent candidate for ED treatment and provide an alternative ED treatment for many patients.[19] The benefits of drug repurposing and relevancy to patient population, as well an the potential of Thiothixene outside its to-be-earned psychotropic envelope will also be discussed.[20] The research departs to highlight investigation of Thiothixene as a PDE-5 If the question has not been stated, then as I reread ED and the purpose of this research, it organizes a thought provoking area for discussion, and note that it may provide an even new concept for the treatment of ED, noting there are patients who have failed typical ED treatments.[21]

MATERIAL AND METHODS

Data Collection: Sources of sildenafil analogue

The compounds from a few reliable databases: PubChem, very large and comprehensive, harboring all chemical information available, including a wide array of sildenafil derivatives, ChEMBL for molecules with drug-like properties and established biological activities, and the ZINC Database, a free source of compound. We started wi mercially available compounds that provides a large collection of sildenafil analogs. Besides, we carried out a review of published articles and patents to collect even more derivatives of sildenafil other than those mentioned in the above databases [22]

Ligand – Based virtual screening protocol.

In ligand-based virtual screening, compounds were selected on multiple criteria to highlight potential drug candidates. [23]Chemical diversity was ensured through the assessment of structural variety with Tanimoto similarity coefficients ADMET properties were assessed to rank compounds according to favorable pharmacokinetic profiles for oral bioavailability; biological relevance was taken into account by considering compounds with reported activity against the target of interest; molecular weight between 300-500 Da and lipophilicity within LogP values 2-5 as optimized for pharmacological properties, and availability that allowed ease of experimental validation Candidates for drug repurposing were tested on Ligand-based Screen by using ligand-based virtual screening [24] The approach made use of a known active ligand of an exemplified target as a template compound, and it was used as a template for screening by different similarity measures like LigMate, FitDock-align, Morgan Fingerprint, LSalign, FP2, and FP4, to rank compounds based on their similarity scores and then to pick the top-ranked compounds for further studies in drug repurposing [25]

Docking studies

In one previous drug repurposing project, I attempted to generate a compound library from databases like ZINC and ChEMBL.[26] Subsequently, a pharmacophore model constructed using the active ligand in order to carry out virtual screening using molecular docking and pharmacophore-based methods.[27] After post-docking analysis was done for evaluation of binding modes and interactions, I prioritized high-scoring compounds further for evaluation.[28]

RESULT AND DISCUSSION

Justification for Selecting Thiothixene

Table 1: Justification for Selecting Thiothixene as the Primary Ligand for Designing New Agents Targeting Erectile Dysfunction (ED)

There are a number of good reasons for selecting Thiothixene as a lead ligand in the development of targeted agents for erectile dysfunction (ED). Thiothixene already has a recognized pharmacologic history as an atypical antipsychotic, and it also possesses an early indication of phosphodiesterase-5 (PDE-5) inhibition, suggesting that the drug has potential. Safety has already been established through the drug’s psychiatric use, thereby reducing some of the risk associated with repurposing thiothixene for ED, and oral administration adds to the attractive nature of compliance. Additionally, due to its mechanism, Thiothixene also has the opportunity for some degree of synergy with current ED treatments, which is important in light of current treatment limitations. The recent success of the repurposing of other drugs, such as Sildenafil, adds some degree of validation for the approach with thiothixene. Several of the attributes that were outlined all support continued examination of thiothixene for the treatment of ED.

Result of Ligand-Based Screening using the Drug-Rep platform

Table 2: Matching scores and target interactions of various compounds

The information presented displays the ranking of 20 chemical species alongside their corresponding Drug Bank ID and score. The highest-ranked compound, Sildenafil (DB00203), scored 0.496, followed by Vardenafil (DB00862) with a score of 0.417, and sildenafil (DB06267), which was lower ranked, scored 0.295. The rest chemical species are ranked from 0.274 - 0.216. The compounds also fit into different pharmacological classes; both Sildenafil and Vardenafil are phosphodiesterase inhibitors, Olanzapine and Amisulpride are antipsychotics, and neither Naratriptan, nor Almotriptan are triptans. The highest-ranking compound is Sildenafil (DB00203), which is a common phosphodiesterase type 5 (PDE5) inhibitor indicated for the treatment of erectile dysfunction and pulmonary arterial hypertension. The high indicative score with this dataset suggests it is very relevant or efficacious and is a noteworthy compound to be included in this dataset.

Results of quality improvement by pdb redo server

Table 3: Validation metrics from PDB-RED

PDB-REDO confirmed the refinement of the model and model quality measures showed a significant improvement from the previous model. The R-factor improved from 0.2052 to 0.1674 (the lower the number the better the fitting the model) and R-free improved from 0.2374 to 0.1961 (the lower the numbers have better fitting model). These values show improvement of fitting the model to the experimental measurements. Interestingly, the bond length RMS Z-score improved from 0.284 to 0.521 and bond angle RMS Z-score improved from 0.596 to 0.775, which indicate that there was increase geometric strain realized in the model. In regard to model quality, there was significant improvement in the normality of the Ramachandran plot from 48 to 93 percentile as well as slight improvement in rotamer normality from 59 to 91 percentile, which reflects greater normality in side-chain and backbone conformations. Other quality measures, such as coarse packing (99) and fine packing (95 to 96) showed no significant change. Bump severity improved from 44 to 67 and hydrogen bond satisfaction slightly improved from 75 to 79%.

Figure 1: Comparative Analysis of Model Quality Metrics: Original vs. PDB-REDO Refinement

The box plots provide a comparison of the original and PDB-REDO data sets on three measures of structural quality: R-Free, the Ramachandran Plot, and Rotamer quality. Each of these three measures provides a consistent indication of structural quality, with the PDB-REDO data being superior. The lower median R-Free values suggest improved quality of the refinement, while the higher Z-scores from the Ramachandran Plot and Rotamer quality indicate increased quality in terms of geometry and conformation. All of this provides evidence for the effectiveness of the PDB-REDO process to improve protein structure models, which is a crucial step in structural biology research. If you'd like a deeper look, please let us know.

Figure 2: Kleywegt – like plot

Figure (2) is a plot similar to Kleywegt´s. It describes the distribution of the phi (Φ) and psi (Ψ) dihedral angles of the amino acids in the protein conformation represented by kids. As indicated by the colour ramp with red as preferred conformation and the scattered blue and orange dots as residues with some stereochemical quality and constraints the back bones of the structure.

Results of Docking studies

Table4: Binding Affinity Analysis of Drug bank compounds to target pockets: Identification of Potential drug candidates.

The updated table relating to binding affinity analysis shows drug candidates sorted from Drug Bank compounds each targeting the individual pockets. A few compounds, for instance, DB01241 (Score: -7.1 in Pocket C1) and DB01187 (Score: -6.7 in Pocket C1), had binding affinity scores above -5.5 indicating to us that they were strong drug candidates that may warrant future investigation. Other compounds like DB00410 (Score: -5.8 in Pocket C3) and DB13966 (Score: -5.8 in Pocket C3) had interesting scores regarding potential future drugs. Within the table's displayed candidate compounds, each compound score varied across pockets and chains, so this may suggest a potential for these drugs to stabilize or interact differently to support the pocket specificity in drug development that was discussed. The drug candidate information depicted on this table may allow researchers to simply select compounds for targeted therapeutics resulting in use based on data. Let me know if you would like further to describe this information!

Figure 3: Cavities found in protein

The evaluation of drug candidates within Drug Bank is illustrated in the table according to their binding breath to target pockets. DB01241 (Score: -7.1), and DB01187 (Score: -6.7) showed the highest binding score for Pocket C1 which could support further evaluation. DB00410 and DB013966 (Score: -5.8) provide the same ranking for Pocket C3 at the top, and warrant further evaluation. Interestingly, the binding scores differentiated between different pockets (C1, C3 and C4) but did not reflect their respective ability to bind. The variation in binding affinity between pockets indicates that drug candidates consistently show a different potential mode of action between pockets and should always be considered to be drug pocket binding. The initial binding model provides the basis for the identification of promising drug compounds to develop for future therapeutic use. Please let me know if you want to hear more!

Figure (4) Molecular Docking of Sildenafil: key binding interactions for Erectile dysfunction disease

Figure (5) Interaction analysis of Thiothixen